Method for the preparation of tetrahydrobenzothiepines

ABSTRACT

Among its several embodiments, the present invention provides an improved process for the preparation of tetrahydrobenzothiepine-1,1-dioxide compounds; the provision of a process for preparing a diastereomeric mixture of tetrahydrobenzothiepine-1,1-dioxide compounds from a single diastereomer of such compounds; the provision of a process for the preparation of 3-bromo-2-substituted propionaldehyde compounds; and the provision of a process for the preparation of 3-thio-2-substituted propionaldehyde compounds.

This application claims benefit of Provisional application No.60/188,361 filed on Mar. 10, 2000.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the preparation of apical sodium co-dependentbile acid transporter (ASBT) inhibitors and more particularly to thepreparation of benzothiepine ASBT inhibitors. This invention especiallyrelates to methods of preparing tetrahydrobenzothiepine oxide ASBTinhibitors.

2. Description of Related Art

It is well established that agents which inhibit the transport of bileacids across the tissue of the ileum can also cause a decrease in thelevels of cholesterol in blood serum. Stedronski, in “Interaction ofbile acids and cholesterol with nonsystemic agents havinghypocholesterolemic properties,” Biochimica et Biophysica Acta, 1210(1994) 255-287 discusses biochemistry, physiology, and known activeagents surrounding bile acids and cholesterol. Bile acids are activelytransported across the tissue of the ileum by an apical sodiumco-dependent bile acid transporter (ASBT), alternatively known as anileal bile acid transporter (IBAT).

A class of ASBT-inhibiting compounds that was recently discovered to beuseful for influencing the level of blood serum cholesterol comprisestetrahydrobenzothiepine oxides (THBO compounds, PCT Patent ApplicationNo. WO 96/08484). Further THBO compounds useful as ASBT inhibitors aredescribed in PCT Patent Application No. WO 97/33882. Additional THBOcompounds useful as ASBT inhibitors are described in U.S. Pat. No.5,994,391. Still further THBO compounds useful as ASBT inhibitors aredescribed in PCT Patent Application No. WO 99/64409. Included in theTHBO class are tetrahydrobenzothiepine-1-oxides andtetrahydrobenzothiepine-1,1-dioxides. THBO compounds possess chemicalstructures in which a phenyl ring is fused to a seven-member ring.

Published methods for the preparation of THBO compounds include thesynthesis through an aromatic sulfone aldehyde intermediate. For example1-(2,2-dibutyl-3-oxopropylsulfonyl)-2-((4-methoxyphenyl)methyl)benzene(29) was cyclized with potassium t-butoxide to formtetrahydrobenzothiepine-1,1-dioxide (syn-24) as shown in Eq. 1.

Compound 29 was prepared by reacting 2-chloro-5-nitrobenzoic acidchloride with anisole in the presence of aluminum trichloride to producea chlorobenzophenone compound; the chlorobenzophenone compound wasreduced in the presence of trifluoromethanesulfonic acid andtriethylsilane to produce a chlorodiphenylmethane compound; thechlorodiphenylmethane compound was treated with lithium sulfide and2,2-dibutyl-3-(methanesulfonato)propanal to produce1-(2,2-dibutyl-3-oxopropylthio)-2-((4-methoxyphenyl)methyl)-4-dimethylaminobenzene(40); and 40 was oxidized with m-chloroperbenzoic acid to produce 29.The first step of that method of preparing compound 29 requires the useof a corrosive and reactive carboxylic acid chloride that was preparedby the reaction of the corresponding carboxylic acid with phosphoruspentachloride. Phosphorus pentachloride readily hydrolyzes to producevolatile and hazardous hydrogen chloride. The reaction of2,2-dibutyl-3-(methanesulfonato)propanal with the lithium sulfide andthe chlorodiphenylmethane compound required the intermediacy of a cyclictin compound to make the of 2,2-dibutyl-3-(methanesulfonato)propanal.The tin compound is expensive and creates a toxic waste stream.

In WO 97/33882 compound syn-24 was dealkylated using boron tribromide toproduce the phenol compound 28. Boron tribromide is a corrosive andhazardous material that generates hydrogen bromide gas and requiresspecial handling. Upon hydrolysis, boron tribromide also produces boratesalts that are costly and time-consuming to separate and dispose of.

An alternative method of preparing THBO compounds was described in WO97/33882, wherein a 1,3-propanediol was reacted with thionyl chloride toform a cyclic sulfite compound. The cyclic sulfite compound was oxidizedto produce a cyclic sulfate compound. The cyclic sulfate was condensedwith a 2-methylthiophenol that had been deprotonated with sodiumhydride. The product of the condensation was a (2-methylphenyl)(3′-hydroxypropyl)thioether compound. The thioether compound wasoxidized to form an thioether aldehyde compound. The thioether aldehydecompound was further oxidized to form an aldehyde sulfone compound whichin turn was cyclized in the presence of potassium t-butoxide to form a4-hydroxytetrahydrobenzothiepine 1,1-dioxide compound. This cyclicsulfate route to THBO compounds requires an expensive catalyst.Additionally it requires the use of SOCl₂, which in turn requiresspecial equipment to handle.

PCT Patent Application No. WO 97/33882 describes a method by which thephenol compound 28 was reacted at its phenol hydroxyl group to attach avariety of functional groups to the molecule, such as a quaternaryammonium group. For example, (4R,5R)-28 was reacted with1,4-bis(chloromethyl)benzene (?,??′-dichloro-p-xylene) to produce thechloromethyl benzyl ether (4R,5R)-27. Compound (4R,5R)-27 was treatedwith diazabicyclo[2.2.2]octane (DABCO) to produce(4R,5R)-1-((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-1-azoniabicyclo[2.2.2]octanechloride (41). This method suffers from low yields because of apropensity for two molecules of compound (4R,5R)-28 to react with onemolecule of 1,4-bis(chloromethyl)benzene to form a bis(benzothiepine)adduct. Once the bis-adduct forms, the reactive chloromethyl group ofcompound (4R,5R)-27 is not available to react with an amine to form thequaternary ammonium product.

A method of preparing enantiomerically enriched tetrahydrobenzothiepineoxides is described in PCT Patent Application No. WO 99/32478. In thatmethod, an aryl-3-hydroxypropylsulfide compound was oxidized with anasymmetric oxidizing agent, for example(1R)-(−)-(8,9-dichloro-10-camphorsulfonyl)oxaziridine, to yield a chiralaryl-3-hydroxypropylsulfoxide. Reaction of thearyl-3-hydroxypropylsulfoxide with an oxidizing agent such as sulfurtrioxide pyridine complex yielded an aryl-3-propanalsulfoxide. Thearyl-3-propanalsulfoxide was cyclized with a base such as potassiumt-butoxide to enantioselectively produce atetrahydrobenzothiepine-1-oxide. The tetrahydrobenzothiepine-1-oxide wasfurther oxidized to produce a tetrahydrobenzothiepine-1,1-dioxide.Although this method could produce tetrahydrobenzothiepine-1,1-dioxidecompounds of high enantiomeric purity, it requires the use of anexpensive asymmetric oxidizing agent.

Some 5-amidobenzothiepine compounds and methods to make them aredescribed in PCT Patent Application Number WO 92/18462.

In Synlett, 9, 943-944(1995) 2-bromophenyl 3-benzoyloxy-1-buten-4-ylsulfone was treated with tributyl tin hydride and AIBN to produce3-benzoyloxytetrahydrobenzothiepine-1,1-dioxide.

SUMMARY OF THE INVENTION

The ongoing work in the area of tetrahydrobenzothiepine synthesis andthe utility of 4-hydroxy-5-phenyltetrahydrobenzothiepine-1,1-dioxidecompounds as cholesterol-lowering therapeutics point to the continuingneed for economical and practical methods to prepare these compounds.

We now report a novel method for preparing tetrahydrobenzothiepinecompounds. Among the several embodiments of the present invention may benoted the provision of an improved process for the preparation oftetrahydrobenzothiepine-1,1-dioxide compounds; the provision of aprocess for preparing a diastereomeric mixture oftetrahydrobenzothiepine-1,1-dioxide compounds from a single diastereomerof such compounds; the provision of a process for the preparation of3-bromo-2-substituted propionaldehyde compounds; and the provision of aprocess for the preparation of 3-thio-2-substituted propionaldehydecompounds.

Briefly, therefore, the present invention is directed to a method forthe preparation of a benzylammonium compound having the structure ofFormula 60

wherein the method comprises treating a benzyl alcohol ether compoundhaving the structure of Formula 61

under derivatization conditions to form a derivatized benzyl ethercompound having the structure of Formula 62

and contacting the derivatized benzyl ether compound with an aminehaving the structure of Formula 42

under amination conditions thereby producing the benzylammonium compoundor a derivative thereof, wherein:

R¹ and R² independently are C₁ to about C₂₀ hydrocarbyl;

R³, R⁴, and R⁵ independently are selected from the group consisting of Hand C₁ to about C₂₀ hydrocarbyl, wherein optionally one or more carbonatom of the hydrocarbyl is replaced by O, N, or S, and whereinoptionally two or more of R³, R⁴, and R⁵ taken together with the atom towhich they are attached form a cyclic structure;

R⁹ is selected from the group consisting of H, hydrocarbyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl,polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle,quaternary heteroaryl, OR³, NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³,SO₃R³, oxo, CO₂R³, CN, halogen, NCO, CONR³R⁴, SO₂OM, SO₂NR³R⁴,PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻, S⁺R³R⁴A⁻, and C(O)OM;

R²³ and R²⁴ are independently selected from the substituentsconstituting R³ and M;

n is a number from 0 to 4;

A⁻ is a pharmaceutically acceptable anion and M is a pharmaceuticallyacceptable cation; and

X is a nucleophilic substitution leaving group.

The present invention is also directed to a method for the preparationof a benzylammonium compound having the structure of Formula 1

wherein the method comprises treating a benzyl alcohol ether compoundhaving the structure of Formula 6

under derivatization conditions to form a derivatized benzyl ethercompound having the structure of Formula 2

and contacting the derivatized benzyl ether compound with an aminehaving the structure of Formula 42:

under amination conditions thereby producing the benzylammonium compoundor a derivative thereof, wherein R¹, R², R³, R⁴, R⁵, and X are definedabove.

The invention is further directed to a method for the preparation of abenzylammonium compound having the structure of Formula 1 wherein themethod comprises the steps of: treating a protected phenol compoundhaving the structure of Formula 14

with a substituted benzoyl compound having the structure of Formula 15

under acylation conditions to produce a substituted benzophenonecompound having the structure of Formula 13

reducing the substituted benzophenone compound to produce a substituteddiphenyl methane compound having the structure of Formula 11

coupling the substituted diphenyl methane compound with a substitutedpropionaldehyde compound having the structure of Formula 12

in the presence of a source of sulfur to form a nitro sulfide aldehydecompound having the structure of Formula 10

oxidizing the nitro sulfide aldehyde compound to form a nitro sulfonealdehyde compound having the structure of Formula 9

reductively alkylating the nitro sulfone aldehyde compound to form anamino sulfone aldehyde compound having the structure of Formula 8

treating the amino sulfone aldehyde compound under cyclizationconditions to form protected phenol compound having the structure ofFormula 7

deprotecting the protected phenol compound to form a phenol compoundhaving the structure of Formula 4

coupling the phenol compound with a substituted xylene having thestructure of Formula 5

under substitution conditions to produce a benzyl alcohol ether compoundhaving the structure of Formula 6 treating the benzyl alcohol ethercompound under derivatization conditions to produce a derivatized benzylether compound having the structure of Formula 2; and treating thederivatized benzyl ether compound with an amine having the structure ofFormula 42 under amination conditions to produce the benzylammoniumcompound 1; wherein:

R¹, R², R³, R⁴, and R⁵ are as defined above; R⁶ is a protecting group, Xand X⁴ independently are nucleophilic substitution leaving groups, X² isselected from the group consisting of chloro, bromo, iodo,methanesulfonato, toluenesulfonato, benzenesulfonato, andtrifluoromethanesulfonato;

X³ is an aromatic substitution leaving group; and

X⁵ is selected from the group consisting of hydroxy and halo.

The present invention is also directed to a method for the preparationof a benzylammonium compound having the structure of Formula 1 whereinthe method comprises a step in which an acetal compound having thestructure of Formula 18

is thermolyzed to form an alkenyl sulfone aldehyde compound having thestructure of Formula 16

wherein R¹ and R⁶ are as defined above; R⁷ is selected from the groupconsisting of H and C₁ to about C₁₇ hydrocarbyl; and R¹³ is selectedfrom the group consisting of H and C₁ to about C₂₀ hydrocarbyl.

In another embodiment, the present invention is directed to a method oftreating a diastereomer of a tetrahydrobenzothiepine compound having thestructure of Formula 22

wherein Formula 22 comprises a (4,5)-diastereomer selected from thegroup consisting of a (4S,5S) diastereomer, a (4R,5R) diastereomer, a(4R,5S) diastereomer, and a (4S,5R) diastereomer, to produce a mixturecomprising the (4S,5S) diastereomer and the (4R,5R) diastereomer,wherein the method comprises contacting a base with a feedstockcomposition comprising the diastereomer of the tetrahydrobenzothiepinecompound, thereby producing a mixture of diastereomers of thetetrahydrobenzothiepine compound; and wherein:

R⁸ is selected from the group consisting of H, hydrocarbyl, heterocycle,((hydroxyalkyl)aryl)alkyl, ((cycloalkyl)alkylaryl)alkyl,((heterocycloalkyl)alkylaryl)alkyl, ((quaternaryheterocycloalkyl)alkylaryl)alkyl, heteroaryl, quaternary heterocycle,quaternary heteroaryl, and quaternary heteroarylalkyl,

wherein hydrocarbyl, heterocycle, heteroaryl, quaternary heterocycle,quaternary heteroaryl, and quaternary heteroarylalkyl optionally haveone or more carbons replaced by a moiety selected from the groupconsisting of O, NR³, N⁺R³R⁴A⁻, S, SO, SO₂, S⁺R³A⁻, PR³, P⁺R³R⁴A⁻,P(O)R³, phenylene, carbohydrate, amino acid, peptide, and polypeptide,and

R⁸ is optionally substituted with one or more moieties selected from thegroup consisting of sulfoalkyl, quaternary heterocycle, quaternaryheteroaryl, OR³, NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³, SO₃R³, oxo,CO₂R³, CN, halogen, CONR³R⁴, SO₂OM, SO₂NR³R⁴, PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻,S⁺R³R⁴A⁻, and C(O)OM;

R¹, R², R³, R⁴, R⁵, R⁹, R²³ and R²⁴, n, A⁻, and M are as defined above;

X⁷ is S, NH, or O; and

x is 1 or 2.

In yet another embodiment, the present invention is directed to a methodof treating a diastereomer of a tetrahydrobenzothiepine compound havingthe structure of Formula (22), wherein the method comprises treating thediastereomer of the tetrahydrobenzothiepine compound under eliminationconditions to produce a dihydrobenzothiepine compound having thestructure of Formula 23

and oxidizing the dihydrobenzothiepine compound to produce the mixtureof diastereomers, wherein:

R¹, R², R⁸, R⁹, X⁷, and n are as defined above; and

x is 0, 1, or 2.

Another embodiment of the present invention is directed to a method forthe preparation of a substituted propionaldehyde compound having thestructure of Formula 12 wherein the method comprises oxidizing asubstituted propanol compound having the structure of Formula 35

wherein R¹ and R² are as defined above, and X⁴ is a nucleophilicsubstitution leaving group.

In another embodiment, the present invention is directed toward acompound having the structure of Formula (2) wherein R¹ and R²independently are C₁ to about C₂₀ hydrocarbyl and X is selected from thegroup consisting of Br, I, and a nucleophilic substitution leaving groupcovalently bonded to the compound via an oxygen atom.

In another embodiment, the present invention provides a crystalline formof a tetrahydrobenzothiepine compound having the structure of Formula 71

or an enantiomer thereof wherein the crystalline form has a meltingpoint or a decomposition point of about 278° C. to about 285° C.

Another embodiment of the present invention provides a crystalline formof a tetrahydrobenzothiepine compound wherein thetetrahydrobenzothiepine compound has the structure of Formula 71 andwhich after a sample of the crystalline form is dried at essentially 0%relative humidity at about 25° C. under a purge of essentially drynitrogen until the sample exhibits essentially no weight change as afunction of time, the sample gains less than 1% of its own weight whenequilibrated under about 80% relative humidity air at about 25° C.Preferably the crystal form of the present invention comprises a(4R,5R)-enantiomer of compound 71.

Still another embodiment of the present invention provides a crystallineform of a tetrahydrobenzothiepine compound wherein thetetrahydrobenzothiepine compound has the structure of Formula 71 or anenantiomer thereof and wherein the crystalline form is produced bycrystallizing the tetrahydrobenzothiepine compound from a solventcomprising methyl ethyl ketone. Preferably the crystal form of thepresent invention comprises a (4R,5R)-enantiomer of compound 71.

In another embodiment, the present invention provides a method for thepreparation of a crystalline form of a tetrahydrobenzothiepine compoundhaving the structure of Formula 63

wherein the method comprises crystallizing the tetrahydrobenzothiepinecompound from a solvent comprising a ketone (for example methyl ethylketone or acetone, preferably methyl ethyl ketone), and wherein R¹, R²,R³, R⁴, R⁵, R⁹, and n are defined above. In Formula 63 Q⁻ is apharmaceutically acceptable anion.

In another embodiment, the present invention provides a method for thepreparation of a product crystal form of a tetrahydrobenzothiepinecompound having the compound structure of Formula 41 wherein the productcrystal form has a melting point or a decomposition point of about 278°C. to about 285° C., wherein the method comprises applying heat to aninitial crystal form of the tetrahydrobenzothiepine compound wherein theinitial crystal form has a melting point or a decomposition point ofabout 220° C. to about 235° C., thereby forming the product crystalform.

Further scope of the applicability of the present invention will becomeapparent from the detailed description provided below. However, itshould be understood that the following detailed description andexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows an overall process by which substituted propionaldehydecompound 12 can be prepared.

FIG. 1a shows a representative overall process by which nitro sulfideacetal compound 67 can be prepared and by which compound 67 can be usedto produce compound 29.

FIG. 2 shows a process by which 2,2-dibutyl-3-bromopropionaldehyde canbe prepared using the methods of the present invention.

FIG. 3 shows an overall process for the preparation of benzylammoniumcompound 1.

FIG. 4 shows an overall process for the preparation of diphenyl methanecompound 11.

FIG. 5 shows a method in which an enantiomerically enrichedtetrahydrobenzothiepine oxide 24 (for example (4R,5R)-24) can be used incombination with the methods of the present invention to prepare anenantiomerically enriched benzylammonium compound.

FIG. 6 shows representative X-ray powder diffraction patterns for Form I(plot (a)) and Form II (plot (b)) of compound 41. Horizontal axis valuesare in degrees 2 theta.

FIG. 7 shows representative Fourier transform infrared (FTIR) spectrafor Form I (plot (a)) and Form II (plot (b)) of compound 41. Horizontalaxis values are in cm⁻¹.

FIG. 8 shows representative solid state carbon-13 nuclear magneticresonance (NMR) spectra for Form I (plot (a)) and Form II (plot (b)) ofcompound 41. Horizontal axis values are in ppm.

FIG. 9 shows representative differential scanning calorimetry profilesfor Form I (plot (a)) and Form II (plot (b)) of compound 41.

FIG. 10 shows water sorption isotherms for Form I (plot (a)) and Form II(plot(b)) of compound 41.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following detailed description is provided to aid those skilled inthe art in practicing the present invention. Even so, this detaileddescription should not be construed to unduly limit the presentinvention as modifications and variations in the embodiments discussedherein can be made by those of ordinary skill in the art withoutdeparting from the spirit or scope of the present inventive discovery.

The contents of each of the references cited herein, including thecontents of the references cited within these primary references, areherein incorporated by reference in their entirety.

a. Definitions

The following definitions are provided in order to aid the reader inunderstanding the detailed description of the present invention:

“Hydrocarbyl” means an organic chemical group composed of carbon andhydrogen atoms. Without meaning to limit its definition, the termhydrocarbyl includes alkyl, alkenyl, alkynyl, aryl, cycloalkyl,arylalkyl, alkylarylalkyl, carbocycle, and polyalkyl.

“Alkyl,” “alkenyl,” and “alkynyl” unless otherwise noted are eachstraight chain or branched chain hydrocarbon groups of from one to abouttwenty carbons for alkyl or two to about twenty carbons for alkenyl andalkynyl in the present invention and therefore mean, for example,methyl, ethyl, propyl, butyl, pentyl or hexyl and ethenyl, propenyl,butenyl, pentenyl, or hexenyl and ethynyl, propynyl, butynyl, pentynyl,or hexynyl respectively and isomers thereof.

“Aryl” means a fully unsaturated mono- or multi-ring carbocycle,including, but not limited to, substituted or unsubstituted phenyl,naphthyl, or anthracenyl.

“Heterocycle” means a saturated or unsaturated mono- or multi-ringcarbocycle wherein one or more carbon atoms can be replaced by N, S, P,or O. This includes, for example, the following structures:

wherein Z, Z¹, Z² or Z³ is C, S, P, O, or N, with the proviso that oneof Z, Z¹, Z² or Z³ is other than carbon, but is not O or S when attachedto another Z atom by a double bond or when attached to another O or Satom. Furthermore, the optional substituents are understood to beattached to Z, Z¹, Z² or Z³ only when each is C.

The term “heteroaryl” means a fully unsaturated heterocycle.

In either “heterocycle” or “heteroaryl,” the point of attachment to themolecule of interest can be at the heteroatom or elsewhere within thering.

The term “quaternary heterocycle” means a heterocycle in which at leastone heteroatom, for example, O, N, S, or P, has such a number of bondsthat the heteroatom is positively charged. The point of attachment ofthe quaternary heterocycle to the molecule of interest can be at aheteroatom or elsewhere.

The term “quaternary heteroaryl” means a heteroaryl in which at leastone heteroatom, for example, O, N, S, or P, has such a number of bondsthat the heteroatom is positively charged. The point of attachment ofthe quaternary heteroaryl to the molecule of interest can be at aheteroatom or elsewhere.

The term “halogen” means a fluoro, chloro, bromo or iodo group.

The term “haloalkyl” means alkyl substituted with one or more halogens.

The term “cycloalkyl” means a mono- or multi-ringed carbocycle whereineach ring contains three to ten carbon atoms, and wherein any ring cancontain one or more double or triple bonds. Examples include radicalssuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl,and cycloheptyl. The term “cycloalkyl” additionally encompasses spirosystems wherein the cycloalkyl ring has a carbon ring atom in commonwith the seven-membered heterocyclic ring of the benzothiepine.

The term “oxo” means a doubly bonded oxygen.

The term “polyalkyl” means a branched or straight hydrocarbon chainhaving a molecular weight up to about 20,000, more preferably up toabout 10,000, most preferably up to about 5,000.

The term “arylalkyl” means an aryl-substituted alkyl radical such asbenzyl. The term “alkylarylalkyl” means an arylalkyl radical that issubstituted on the aryl group with one or more alkyl groups.

The term “heterocyclylalkyl” means an alkyl radical that is substitutedwith one or more heterocycle groups. Preferable heterocyclylalkylradicals are “lower heterocyclylalkyl” radicals having one or moreheterocycle groups attached to an alkyl radical having one to ten carbonatoms.

The term “heteroarylalkyl” means an alkyl radical that is substitutedwith one or more heteroaryl groups. Preferable heteroarylalkyl radicalsare “lower heteroarylalkyl” radicals having one or more heteroarylgroups attached to an alkyl radical having one to ten carbon atoms.

The term “quaternary heterocyclylalkyl” means an alkyl radical that issubstituted with one or more quaternary heterocycle groups. Preferablequaternary heterocyclylalkyl radicals are “lower quaternaryheterocyclylalkyl” radicals having one or more quaternary heterocyclegroups attached to an alkyl radical having one to ten carbon atoms.

The term “quaternary heteroarylalkyl” means an alkyl radical that issubstituted with one or more quaternary heteroaryl groups. Preferablequaternary heteroarylalkyl radicals are “lower quaternaryheteroarylalkyl” radicals having one or more quaternary heteroarylgroups attached to an alkyl radical having one to ten carbon atoms.

The term “alkoxy” means a radical comprising an alkyl radical that isbonded to an oxygen atom, such as a methoxy radical. More preferredalkoxy radicals are “lower alkoxy” radicals having one to ten carbonatoms. Examples of such radicals include methoxy, ethoxy, propoxy,isopropoxy, butoxy and tert-butoxy.

The term “carboxy” means the carboxy group, —CO₂H, or its salts.

The term “carboalkoxyalkyl” means an alkyl radical that is substitutedwith one or more alkoxycarbonyl groups. Preferable carboalkoxyalkylradicals are “lower carboalkoxyalkyl” radicals having one or morealkoxycarbonyl groups attached to an alkyl radical having one to sixcarbon atoms.

When used in combination, for example “alkylaryl” or “arylalkyl,” theindividual terms listed above have the meaning indicated above.

As used herein, Me means methyl; Et means ethyl; Pr means propyl; i-Pror Pr^(i) each means isopropyl; Bu means butyl; t-Bu or Bu^(t) eachmeans tert-butyl; Py means pyridine.

The term “derivative” means a compound containing a structural moietysimilar to that of another chemical. The term derivative includes, forexample, a conjugate acid, a conjugate base, a free base, a free acid, aracemate, a salt, an ester, a compound protected with a protectinggroup, a tautomer, a stereoisomer, a substituted compound, and aprodrug.

The term “stereoisomer,” where a compound has at least one chiralcenter, includes each enantiomer and each diastereomer. Where a compoundhas an aliphatic double bond, the term “stereoisomer” includes each cisor Z isomer as well as each trans or E isomer.

In structural drawings, when a chemical bond is represented as an openwedge, such a representation means that the bond can either go into theplane of the page or come out of the plane of the page. When in astructural drawing two or more bonds are represented in the drawing asopen wedges (e.g., the structure of

Formula 1) the bonds so indicated are in a syn conformation; that is tosay all such bonds go into the plane of the page or all such bonds comeout of the plane of the page.

In structural drawings, when a chemical bond is represented as afilled-in blackened wedge, such a representation means that the bond iscoming out of the plane of the page and represents a specificstereochemistry.

In structural drawings, when a chemical bond is represented as a dashedwedge (e.g., the structure of compound 41), such a representation meansthat the bond is going into the plane of the page and represents aspecific stereochemistry.

In structural drawings, when a chemical bond is represented as a wavyline (e.g., the structure of compound 24), such a representation meansthat the bond can assume any stereochemistry and can be syn, anti, cis,or trans with any of its neighboring bonds.

b. Process Details

In accordance with the present invention, a process has been discoveredfor economically preparing a benzylammonium compound having thestructure of Formula 1 wherein the method comprises treating a benzylalcohol ether compound having the structure of Formula 6 underderivatization conditions to form a derivatized benzyl ether compoundhaving the structure of Formula 2 and contacting the derivatized benzylether compound with an amine having the structure of Formula 42 underamination conditions thereby producing the benzylammonium compound or aderivative thereof, wherein: R¹ and R² independently are C₁ to about C₂₀hydrocarbyl; R³, R⁴, and R⁵ independently are selected from the groupconsisting of H and C₁ to about C₂₀ hydrocarbyl, wherein optionally oneor more carbon atom of the hydrocarbyl is replaced by O, N, or S, andwherein optionally two or more of R³, R⁴, and R⁵ taken together with theatom to which they are attached form a cyclic structure; and X is anucleophilic substitution leaving group. The conversion of compound (6)to compound (1) is shown in Eq. 2.

Groups R³, R⁴, and R⁵ independently can vary widely in their structuresand compositions and remain within the scope of the present invention.In one embodiment, R³, R⁴, and R⁵ independently can be H or C₁ to aboutC₂₀ hydrocarbyl. Preferably, R³, R⁴, and R⁵ independently can be H or C₁to about C₁₀ hydrocarbyl; more preferably independently C₁ to about C₁₀hydrocarbyl; still more preferably independently C₁ to about C₅hydrocarbyl. In a preferred embodiment, R³, R⁴, and R⁵ independently canbe methyl, ethyl, or propyl. For example, R³, R⁴, and R⁵ can each bemethyl and the amine of Formula 42 can be trimethylamine. Alternatively,R³, R⁴, and R⁵ can each be ethyl and the amine of Formula 42 can betriethylamine.

In another embodiment, the amine of Formula 42 can comprise aheterocycle as its structure or as one of its substructures. The aminecan have more than one ring and can comprise, for example, a bicyclicheterocycle. In a preferred embodiment, the amine is1,4-diazabicyclo[2.2.2]octane (DABCO) and the benzylammonium compoundhas the structure of Formula 3.

Groups R¹ and R² can also vary widely in the method of the presentinvention. For example, R¹ and R² independently can be C₁ to about C₁₀hydrocarbyl; preferably R¹ and R² are independently C₁ to about C₅hydrocarbyl. In one preferred embodiment R¹ and R² are both butyl.

The benzylammonium compound 1 can be an essentially racemic mixture ofenantiomers, or one enantiomer can preponderate over another enantiomer.For example, when R¹ and R² are both butyl, compound 1 can be anessentially racemic mixture of enantiomers or compound 1 can comprise a(4R,5R) enantiomer that preponderates over a (4S,5S) enantiomer.

In another preferred embodiment one of R¹ and R² is ethyl and the otherof R¹ and R² is butyl. In such a case, compound 1 can be an essentiallyracemic mixture of enantiomers or compound 1 can comprise a (3R)enantiomer that preponderates over a (3S) enantiomer. Alternatively,compound 1 can comprise a (3S) enantiomer that preponderates over a (3R)enantiomer.

X in the structure of Formula 1 can vary widely and can representessentially any nucleophilic leaving group that produces either apharmaceutically acceptable anion or an anion that can be exchanged fora pharmaceutically acceptable anion. In other words, X⁻ is apharmaceutically acceptable anion or an anion that can be exchanged fora pharmaceutically acceptable anion. For example, X can be chloro,bromo, iodo, methanesulfonato, toluenesulfonato, andtrifluoromethanesulfonato. Preferably X is chloro, bromo, or iodo andmore preferably X is chloro.

Pharmaceutically acceptable salts are particularly useful as products ofthe methods of the present invention because of their greater aqueoussolubility relative to a corresponding parent or neutral compound. Suchsalts must have a pharmaceutically acceptable anion or cation. Suitablepharmaceutically acceptable acid addition salts of the compounds of thepresent invention when possible include those derived from inorganicacids, such as hydrochloric, hydrobromic, hydrofluoric, boric,fluoroboric, phosphoric, metaphosphoric, nitric, carbonic (includingcarbonate and hydrogen carbonate anions), sulfonic, and sulfuric acids,and organic acids such as acetic, benzenesulfonic, benzoic, citric,ethanesulfonic, fumaric, gluconic, glycolic, isothionic, lactic,lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic,succinic, toluenesulfonic, tartaric, and trifluoroacetic acids. Thechloride salt is particularly preferred for medical purposes. Suitablepharmaceutically acceptable base salts include ammonium salts, alkalimetal salts such as sodium and potassium salts, and alkaline earth saltssuch as magnesium and calcium salts.

When compound 1 is formed, it can be used as it is prepared or it can befurther processed. For example, anion X⁻ can be exchanged, for exampleby an ion exchange method such as ion exchange chromatography, for anypharmaceutically acceptable anion.

The amination conditions under which compound 2 and compound 42 react toform benzylammonium compound 1 are robust and can vary widely. Forexample, the amination can be performed neat without a solvent, or theamination conditions can comprise a solvent. When a solvent is employed,that solvent can have hydrophilic or hydrophobic properties or it canhave both hydrophilic and hydrophobic properties. When the solventcomprises a hydrophilic solvent, the hydrophilic solvent can comprise,for example, water; a nitrile such as acetonitrile; an ether such astetrahydrofuran, diethyl ether, or methyl t-butyl ether; an alcohol suchas methanol, ethanol, isopropyl alcohol, or butanol; a ketone such asacetone or methyl ethyl ketone; or an ester such as ethyl acetate. Whenthe solvent comprises a hydrophobic solvent, the hydrophobic solvent cancomprise, for example, an aliphatic hydrocarbon solvent such as a C₁ toabout C₂₀ aliphatic hydrocarbon; an aromatic solvent such as benzene,toluene, xylene, or mesitylene; or a halogenated solvent such asmethylene chloride, chloroform, carbon tetrachloride,trifluoromethylbenzene, or chlorobenzene. Alternatively, the solvent cancomprise a blend of hydrophilic and hydrophobic solvents. In onepreferred embodiment the solvent comprises a blend of methyl ethylketone and water. In a further preferred embodiment the solventcomprises a blend of methyl ethyl ketone, toluene, and water.Essentially any solvent that is less nucleophilic than compound 42 canbe used as a solvent in the amination reaction. Preferably the aminationis performed under conditions in which the reagents and product aresubstantially in homogeneous solution during the majority of thereaction.

The amination can proceed over a wide range of temperatures andpreferably is performed within the range of about 0° C. to about 120°C., more preferably about 15° C. to about 110° C., still more preferablyabout 30° C. to about 100° C., and more preferably still about 45° C. toabout 90° C. The amination conveniently can be performed in refluxingsolvent such as refluxing methyl ethyl ketone. Preferably, the refluxingin methyl ethyl ketone is performed at ambient pressure.

The derivatization conditions under which benzyl alcohol ether compound6 is reacted to form a derivatized benzyl ether compound of Formula 2can comprise essentially any conditions known in the art for convertinga benzyl alcohol group into a group that is labile under nucleophilicsubstitution conditions such as amination conditions. For example, thederivatization conditions can comprise contacting compound 6 with ahalogenating agent. Useful halogenating agents include a thionyl halide,a sulfuryl halide, a phosphorus trihalide, a phosphorus pentahalide, anoxalyl halide, and a hydrogen halide. A halogenating agent useful in thepresent process is preferably a chlorinating agent or a brominatingagent, and more preferably a chlorinating agent. For example, thehalogenating agent can be thionyl chloride, phosphorus trichloride,phosphorus pentachloride, or hydrogen chloride; preferably thehalogenating agent is selected among thionyl chloride, phosphorustrichloride, and phosphorus pentachloride. More preferably thehalogenating agent is thionyl chloride. Alternatively, the halogenatingagent can comprise a mixture of a phosphine such as triphenylphosphineand a carbon tetrahalide such as carbon tetrachloride. The halogenatingagent can be added to the reaction mixture in any form. For example thehalogenating agent can be added as a solid or as a liquid (for exampleas a liquid above the melting point of the halogenating agent or as asolution in a solvent) or the halogenating agent can be contacted withthe reaction mixture as a gas under ambient, subambient, or elevatedpressure.

When the halogenating agent is thionyl chloride, the halogenationreaction can be performed under a wide variety of conditions. Thereaction can be run neat or it can be run in the presence of a solvent.A particularly useful solvent is an aprotic solvent. For example, thesolvent can comprise an aromatic solvent, a chlorinated solvent, anether, an amide, an ester, or a hydrocarbon. Preferred solvents includemethylene chloride, chloroform, carbon tetrachloride, chlorobenzene,trifluoromethylbenzene, tetrahydrofuran, diethyl ether, ethyl acetate,and N,N-dimethylacetamide. When the halogenating agent is thionylchloride, the reaction can be performed at essentially any convenienttemperature. Preferably the reaction can run at a temperature of about0° C. to about 150° C., more preferably about 10° C. to about 125° C.,more preferably still about 15° C. to about 100° C., still morepreferably about 20° C. to about 75° C., and more preferably yet about20° C. to about 50° C.

Alternatively, the derivatization conditions under which compound 6 isreacted to form compound 2 can comprise sulfonating the hydroxy group ofcompound 6 with a sulfonation reagent to form a sulfonated compound, andthen treating the sulfonated compound with a source of halide such as ahydrogen halide or a halide salt to form compound 2.

In another embodiment, the derivatization conditions can compriseconditions under which the benzyl hydroxyl group is converted into anoxygen leaving group, for example methanesulfonato, toluenesulfonato,benzenesulfonato, or trifluoromethanesulfonato. Benzyl alcohol ethercompound 6 can for example be treated with a sulfonation reagent such asan alkyl sulfonyl halide reagent or an aryl sulfonyl halide reagent.Such alkyl or aryl sulfonyl halide reagents can include amethanesulfonyl halide, a toluenesulfonyl halide, a benzenesulfonylhalide, or a trifluoromethanesulfonyl halide. Preferably the reagent isan alkyl sulfonyl chloride reagent, an aryl sulfonyl chloride reagent,an alkyl sulfonyl bromide reagent, or an aryl sulfonyl bromide reagent.More preferably the sulfonyl halide reagent is a sulfonyl chloridereagent such as methanesulfonyl chloride, toluenesulfonyl chloride,benzenesulfonyl chloride, or trifluoromethanesulfonyl chloride.

In the process of the present invention, the benzyl alcohol ethercompound 6 can be used as an essentially racemic mixture of enantiomersor one enantiomer can preponderate over another enantiomer. For example,compound 6 can have a predominantly (4R,5R) absolute configuration or itcan have a predominantly (4S,5S) absolute configuration. Alternatively,compound 6 can comprise a blend of (4R,5R) and (4S,5S) absoluteconfigurations.

The preparative method of the present invention can further comprise astep wherein a phenol compound having the structure of Formula 4 iscontacted with a substituted xylene compound having the structure ofFormula 5 under substitution conditions to produce a benzyl alcoholether compound having the structure of Formula 6 wherein X² is a leavinggroup. Phenol compound 4 can comprise an essentially racemic mixture orit can comprise predominantly an absolute configuration of (4R,5R).Alternatively, compound 4 can comprise predominantly an absoluteconfiguration of (4S,5S). The conversion of compound 4 into compound 6is shown in Eq. 3.

X² can be essentially any leaving group known in the art fornucleophilic substitution at benzylic carbon. For example, X² can behalo or a sulfonato group such as methanesulfonato, toluenesulfonato,benzenesulfonato, or trifluoromethanesulfonato. Preferably X² is haloand more preferably it is chloro, bromo, or iodo. More preferably stillX² is chloro.

The conversion of compound 4 into compound 6 can be performed, ifdesired, in the presence of a solvent. Essentially any solvent thatdissolves to some extent the reactants and that is primarilynon-reactive toward the reactants will be useful. For example, thesolvent can comprise an aromatic solvent, an amide, an ester, a ketone,an ether or a sulfoxide. Preferably, the solvent is an aprotic solventsuch as N-methyl pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, or anamide solvent. Preferably the solvent is an amide solvent. Morepreferably the amide is selected from the group consisting ofdimethylformamide and dimethylacetamide; and still more preferably thesolvent is N,N-dimethylacetamide (DMAC).

The conversion of compound 4 into compound 6 can further be performed inthe presence of a base. Useful bases include a metal hydroxide, a metalalcoholate, a metal hydride, an alkyl metal complex, a metal carbonate,and an amide base. Preferably the base comprises a metal hydroxide suchas sodium hydroxide, potassium hydroxide, lithium hydroxide, or calciumhydroxide. More preferably the base is sodium hydroxide. When the baseis a metal carbonate, preferably it is an alkali metal carbonate or analkaline earth metal carbonate. For example the base can be potassiumcarbonate.

The preparative method of the present invention can further comprise adeprotecting step wherein a protected phenol compound having thestructure of Formula 7

is deprotected to form the phenol compound 4, wherein R⁶ is a protectinggroup. The conversion of compound 7 into compound 4 is shown in Eq. 4. Aprotecting group is any chemical group that temporarily blocks areactive site in a molecule while a chemical reaction is selectivelyperformed at another reactive site in the same molecule or at a reactivesite in another molecule residing in the same reaction mixture as theprotected molecule. Many protecting groups described by Greene and Wuts(Protective Groups in Organic Synthesis, 3d ed., John Wiley & Sons,Inc., New York, 1999, pp. 249-287, herein incorporated by reference) areuseful for protecting the phenol functional group in the process of thepresent invention. For example, R⁶ can be a hydrocarbyl group such as amethyl group, an isopropyl group, a t-butyl group, a cyclohexyl group,or a benzyl group; an alkoxymethyl group such as a methoxymethyl groupor a benzyloxymethyl group; an alkylthiomethyl group such as amethylthiomethyl group; a silyl group such as a trimethylsilyl group; anacyl group such as a formyl group, an acetyl group, or a benzoyl group;a carbonate group such as a methyl carbonate group; a phosphinate group;or a sulfonate group. In one embodiment, R⁶ is a C₁ to about C₁₀hydrocarbyl group, preferably a C₁ to about C₁₀ alkyl group, morepreferably a C₁ to about C₅ alkyl group, and still more preferablymethyl.

When R⁶ is a methyl group, a wide variety of conditions can be used inthe deprotecting step. For example the conditions of the deprotectingstep can comprise treating compound 7 with a deprotecting reagent.Without limitation, useful deprotecting reagents include ahalotrimethylsilane such as iodotrimethylsilane; an alkali metal such aslithium or sodium in combination with 18-crown-6; an alkali metalsulfide such as sodium sulfide or lithium sulfide; an alkali metalhalide such as lithium iodide; an aluminum trihalide such as aluminumtribromide; an aluminum trihalide and an alkylthiol such as ethanethiol;a strong acid in combination with a source of nucleophilic sulfur; aboron trihalide such as boron tribromide or boron trichloride; ahydrogen halide such as hydrogen iodide, hydrogen bromide, or hydrogeniodide; or a metal hydrocarbyl thiolate. When the deprotecting reagentcomprises a boron trihalide, preferably it comprises boron tribromide.When the deprotecting reagent is a metal hydrocarbyl thiolate,preferably it is a lithium hydrocarbyl thiolate, more preferably alithium C₁ to about C₁₀ alkyl thiolate, and more preferably stilllithium ethanethiolate. When the deprotecting reagent is a strong acidin combination with a source of nucleophilic sulfur, preferably thestrong acid can for example be sulfuric acid, a sulfonic acid, a Lewisacid, or a phosphorus oxy acid. Preferably the strong acid is sulfuricacid or a sulfonic acid, and more preferably a sulfonic acid. When thestrong acid is a sulfonic acid, preferably it is methanesulfonic acid,trifluoromethanesulfonic acid, benzenesulfonic acid, or toluenesulfonicacid; more preferably the strong acid is methanesulfonic acid. Thesource of nucleophilic sulfur can, for example, be methionine.

In the method of the present invention, compound 7 can be a racemiccompound or it can be used as a mixture of stereoisomers or it can beused as predominantly one of its stereoisomers. Preferably compound 7has an absolute configuration of (4R,5R). Alternatively, compound 7 canhave an absolute configuration of (4S,5S).

When the deprotecting reagent is a sulfonic acid in combination withmethionine, a variety of conditions can be employed in the deprotectingstep of the present method. The reaction can be run substantially neat(substantially without added solvent), or a solvent can be added.Essentially any solvent that dissolves the reagents and that is mostlyunreactive toward the reagents would be useful in this reaction. Usefulsolvents include a hydrocarbon solvent such as an alkane, an aromaticsolvent such as benzene or toluene; a chlorinated solvent such asmethylene chloride, chloroform, carbon tetrachloride, chlorobenzene, ortrifluoromethylbenzene; and inorganic solvents such as SO₂.

The deprotecting step can be performed over a wide range oftemperatures. Preferably the temperature is in the range of about 0° C.to about 150° C., more preferably about 25° C. to about 130° C., stillmore preferably about 50° C. to about 110° C., and more preferably stillabout 65° C. to about 100° C.

In another embodiment, the method of the present invention can furthercomprise a cyclization step wherein an amino sulfur oxide aldehydecompound having the structure of Formula 8a is treated under cyclizationconditions to form a protected phenol compound having the structure ofFormula 7a wherein R¹, R², and R⁶ are defined above, and y is 1 or 2.The cyclization of 8a into 7a is shown in Eq. 5.

The cyclization can be mediated by conditions that comprise treating theamino sulfur oxide aldehyde with a base. Useful bases in this reactioninclude MOR¹¹, a metal hydroxide, or an alkyl metal complex, wherein R¹¹is a C₁ to about C₁₀ hydrocarbyl group and M is an alkali metal.Preferably the base is MOR¹¹. When the base is MOR¹¹, M is preferablylithium or potassium. In a particularly useful embodiment R¹¹ is a C₁ toabout C₁₀ alkyl group, preferably a C₁ to about C₅ alkyl group, morepreferably R¹¹ is methyl, ethyl, isopropyl, or tert-butyl, and stillmore preferably R¹¹ is tert-butyl.

The conditions of the cyclization step can comprise a solvent. Thesolvent can be a hydrophilic solvent and preferably it is a hydrophilicaprotic solvent. The solvent can be, for example, a cyclic or acyclicether such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether,1,4-dioxane, glyme, or diglyme. Preferably the solvent istetrahydrofuran. Alternatively, the solvent can be an alcohol such asmethanol, ethanol, propanol, isopropyl alcohol, butanol, sec-butylalcohol, isobutyl alcohol, or t-butyl alcohol.

The cyclization step can be performed at various temperatures.Preferably the step is performed at a temperature of about −20° C. toabout 50° C., preferably about −10° C. to about 35° C., and morepreferably about 0° C. to about 25° C.

When y is 1, the present method can further comprise an oxidation stepto convert the amino sulfoxide aldehyde (8a where y=1) to the aminosulfone aldehyde (8a where y=2). For example, the oxidation step cancomprise treating the amino sulfoxide aldehyde with sodium hypochlorite.Alternatively, the amino sulfoxide aldehyde can be treated with hydrogenperoxide, preferably in the presence of imidazole andtetraphenylporphyrin Fe(III) chloride. In another alternative, the aminosulfoxide aldehyde can be treated with hydrogen peroxide in the presenceof methyltrioxorhenium. The conversion of the amino sulfoxide aldehydeto the sulfone will also be achieved by treating the sulfoxide withhydrogen peroxide in the presence of acetonitrile and a base such aspotassium carbonate. Another useful oxidation will comprise treating theamino sulfoxide aldehyde with cobalt diacetonylacetonate (Co(acac)₂) inthe presence of O₂ and, for example, isovaleraldehyde. Still anotheruseful oxidation will comprise treating the amino sulfoxide aldehydewith 2-methylpropanal in the presence of O₂. Alternatively, theoxidation will be performed by treating the amino sulfoxide aldehydewith silica gel in the presence of t-butyl hydroperoxide. The conversionwill also occur when the amino sulfoxide aldehyde is treated withperiodic acid in the presence, for example, of ruthenium trichloridehydrate. Alternate conditions for the oxidation can comprise treatingthe amino sulfoxide aldehyde with urea and phthalic anhydride in thepresence of hydrogen peroxide. In another example the oxidation of theamino sulfoxide aldehyde will be carried out by treatment with Oxonemonopersulfate compound (2KHSO₅.KHSO₄.K2SO₄) in the presence of silicagel or wet montmorillonite clay.

Preferably y is 2 during the cyclization step.

In still another embodiment, the method of the present invention canfurther comprise an reductive alkylation step in which a nitro sulfuroxide aldehyde compound having the structure of Formula 9a isreductively alkylated to form the amino sulfur oxide aldehyde compound8b wherein R¹, R², and R⁶ are defined above, and z is 0, 1, or 2.Preferably z is 2. The conditions under which compound 9a is reductivelyalkylated can include, for example, contacting 9a with a source offormaldehyde and a source of H₂ in the presence of a catalyst. Thereductive alkylation is preferably performed at elevated H₂ pressure. Itis useful to perform the reductive alkylation at H₂ pressures rangingfrom about 100 to about 700,000 kPa, preferably from about 200 to about300,000 kPa, more preferably from about 300 to about 100,000 kPa, stillmore preferably from about 350 to about 10,000 kPa, and more preferablystill from about 400 to about 1000 kPa. The conversion of compound 9ainto compound 8b is shown in Eq. 6.

The reductive alkylation described herein can, if preferred, beperformed on an acetal derivative of compound 9a as shown in Eq. 8b.

The source of formaldehyde can be essentially any source that producesthe equivalent of CH₂O. For example, the source of formaldehyde can beformalin, dimethoxymethane, paraformaldehyde, trioxane, or any polymerof CH₂O.

Conveniently the source of formaldehyde can be formalin, and preferablyabout 30% to about 37% formalin.

The catalyst for the reductive alkylation can be either a heterogeneouscatalyst or a homogeneous catalyst. Preferably the catalyst is a metal,for example be a noble metal catalyst. Useful noble metal catalystsinclude Pt, Pd, Ru, and Rh. Preferably the noble metal catalyst is a Pdcatalyst. Alternatively, the metal catalyst can be a nickel catalyst,for example a high-surface area nickel catalyst such as Raney nickel.The catalyst can be a homogeneous catalyst or it can be a heterogeneouscatalyst, preferably a heterogeneous catalyst. When the catalyst is anoble metal catalyst, it can be used either as the metal per se or themetal can be used in combination with a solid support such as carbon.Alternatively, the metal catalyst can be used in combination withanother metal such as an anchor metal or a promoter metal. In aparticularly preferred embodiment, the catalyst comprises Pd on carbon.

An acid can be present in the reaction mixture during the reductivealkylation. Preferably the acid is a strong acid and more preferably astrong mineral acid. For example, the acid can be sulfuric acid.

The reaction mixture can conveniently comprise a solvent during thereductive alkylation. Useful solvents include an alcohol, an aromaticsolvent, an ether solvent, and a halogenated solvent such as ahalogenated aromatic solvent. Preferably the solvent is an alcoholsolvent such as ethanol.

The reductive alkylation reaction can be run at any convenienttemperature, for example from about 0° C. to about 200° C., preferablyfrom about 10° C. to about 150° C., more preferably from about 15° C. toabout 125° C., still more preferably from about 20° C. to about 100° C.,more preferably still from about 25° C. to about 80° C., and morepreferably yet from about 30° C. to about 75° C.

The reductive alkylation can alternatively be performed in two steps.For example, in a first step the nitro group of compound 9a can bereduced to an amino group and then the amino group can be methylated.For example, nitro sulfur oxide aldehyde compound 9a can be reduced toform an aniline sulfur oxide compound having the structure of Formula 39

wherein R¹, R², R⁶ and z are as defined above. The method can furthercomprise a methylation step in which the aniline sulfur oxide compoundis treated under methylation conditions to form the amino sulfur oxidealdehyde compound 8a. The reduction of the nitro group to an amino groupcan be achieved, for example, by catalytic hydrogenation. The catalytichydrogenation to form compound 39 will be achieved, for example bycontacting compound 9a with H₂ in the presence of a hydrogenationcatalyst. A useful hydrogenation catalyst will be, for example, apalladium catalyst such as palladium on carbon (Pd/C). It will be usefulto perform the hydrogenation at H₂ pressures ranging from about 100 toabout 700,000 kPa, preferably from about 200 to about 300,000 kPa, morepreferably from about 300 to about 100,000 kPa, still more preferablyfrom about 350 to about 10,000 kPa, and more preferably still from about400 to about 1000 kPa. The methylation step can be carried out under awide variety of methylation conditions. Alternatively, the reduction of9a to form 39 can be performed under other reduction conditions such astreatment of 9a with iron in the presence of acetic acid or treatment of9a with tin in the presence of hydrochloric acid.

The methylation conditions can comprise, for example, treating compound39 with a methylating reagent such as a methyl halide or a methylsulfonate. Useful methyl halides include methyl chloride, methylbromide, and methyl iodide. Useful methyl sulfonates include methylmethanesulfonate, methyl toluenesulfonate, methyl benzenesulfonate, andmethyl trifluoromethylsulfonate. Alternatively, the methylationconditions can comprise treating compound 39 with a source offormaldehyde in the presence of H₂ and a hydrogenation catalyst.Conditions useful for the reductive alkylation of compound 9a tocompound 8b are also useful for the methylation of compound 39.

In another embodiment, the method of the present invention can furthercomprise an oxidation step in which a nitro sulfide aldehyde compoundhaving the structure of Formula 10 is oxidized to form compound 9awherein R⁶ is a protecting group and z is 1 or 2. Preferably, compound10 is treated under oxidation conditions to form a nitro sulfonealdehyde compound of Formula 9. The oxidation reaction can be carriedout by treating 10 with an oxidizing agent. Useful oxidizing agentsinclude, for example, a peracid, an alkyl hydroperoxide, or hydrogenperoxide. When the oxidizing agent is a peracid, it can conveniently be,for example, peracetic acid or m-chloroperbenzoic acid. Preferably theoxidizing agent comprises peracetic acid. The conversion of compound 10to compound 9a is shown in Eq. 7.

The method of the present invention can also further comprise a step inwhich compound 9a where z is 1 is oxidized to sulfone compound 9. Suchan oxidation can be performed by treating 9a where z is 1 with forexample, a peracid, an alkyl hydroperoxide, or hydrogen peroxide.

During the oxidation step of Eq. 8 it is convenient to protect thealdehyde functional group of compound 10 from oxidation, for example toprevent the formation of the corresponding carboxylic acid. A variety ofprotecting groups are known in the art for protecting aldehydes frombeing oxidized to carboxylic acids and such protecting groups can beemployed in the method of the present invention. Numerous methods ofprotecting aldehydes are described by Greene and Wuts (Protective Groupsin Organic Synthesis, 3d ed., John Wiley & Sons, Inc., New York, 1999,pp. 297-368, herein incorporated by reference) are useful herein. Forexample, the aldehyde group of compound 10 can be protected as an acetalsuch as a dimethyl acetal or a diethyl acetal. Essentially any of theacetal-forming methods described by Greene and Wuts are useful in thepresent invention. It is convenient to protect the aldehyde group of 10as a dimethyl acetal by contacting 10 with trimethyl orthoformate, anacid such as p-toluenesulfonic acid, and methanol. Conveniently, 10 canbe contacted with trimethyl orthoformate, the acid, and methanol in thepresence of a solvent. A useful solvent is benzotrifluoride (BTF). Afterthe oxidation step, the aldehyde group can be deprotected by methodsknown in the art. For example, the dimethyl acetal can be converted tothe aldehyde by treatment with water and an acid such as sulfuric acidor hydrochloric acid.

Alternatively, the method of the present invention can comprise anoxidation step in which the conditions comprise enantioselectiveoxidation conditions. Such enantioselective oxidation conditions aredescribed in PCT Patent Application No. WO 99/32478, herein incorporatedby reference. For example, nitro sulfide aldehyde compound 10 can beenantioselectively oxidized to a chiral nitro sulfoxide aldehydecompound (9a where z is 1). Ring closure of the chiral nitro sulfoxidealdehyde compound by treatment with base (for example a metal alkoxidesuch as potassium t-butoxide) will form selectively one enantiomer orset of diastereomers of the tetrahydrobenzothiepine-1-oxide compoundthat can be further oxidized selectively to predominantly one enantiomeror selectively to a set of diastereomers of thetetrahydrobenzothiepine-1,1-dioxide.

The method of the present invention can further comprise asulfide-forming step in which a substituted diphenyl methane compoundhaving the structure of Formula 11 is coupled with a substitutedpropionaldehyde equivalent compound having the structure of Formula 12ain the presence of a source of sulfur to form the nitro sulfide aldehydecompound 10 wherein R¹, R², and R⁶ are defined above;

R²⁷ is an aldehyde group (—CHO) or a protected aldehyde group such as anacetal;

X³ is an aromatic substitution leaving group; and X⁴ is a nucleophilicsubstitution leaving group. This overall sulfide-forming step is shownin Eq. 8.

Where R²⁷ is an aldehyde group, compound 12a has the structure ofFormula 12.

In the reaction of Eq. 8, it is also possible for R²⁷ to be —CH₂OH (or aprotected alcohol) or —CO₂H (or a protected carboxylic acid). Where R²⁷is —CH₂OH (or a protected alcohol), the addition of compound 12a canconveniently be followed by an oxidation step in which the alcoholfunction is oxidized to an aldehyde or carboxylic acid function. WhereR²⁷ is —CO₂H (or a protected carboxylic acid), the addition of compound12a can conveniently be followed by a reduction step. Alternatively,where R²⁷ is —CO₂H (or a protected carboxylic acid), the addition ofcompound 12a can be followed by a cyclization step and/or a sulfuroxidation step to form a cyclic ketone that can be reduced to alcohol7a.

The source of sulfur can be, for example, a metal sulfide such aslithium sulfide (Li₂S), sodium sulfide (Na₂S), or Na₂S₂. Preferably thesource of sulfur is Na₂S or Li₂S, and more preferably Na₂S. X³ can beessentially any convenient aromatic substitution leaving group. Forexample, X³ can be a halogen, a sulfonato group, or a nitro group.Preferably X³ is a halogen, more preferably Cl or Br, and still morepreferably Cl. When X³ is a sulfonato group, it can be, for example,methanesulfonato, trifluoromethanesulfonato, benzenesulfonato, ortoluenesulfonato; preferably X³ is trifluoromethane-sulfonato. When X³is a sulfonato group, the sulfide-forming reaction is preferably carriedout in the presence of a noble metal such as Pd(0) and a metal sulfide.

X⁴ can be essentially any nucleophilic substitution leaving group that,when displaced, produces an anion that is chemically and physicallycompatible with the reaction conditions. For example, X⁴ can be chloro,bromo, iodo, methanesulfonato, toluenesulfonato, andtrifluoromethanesulfonato. Preferably X⁴ is chloro, bromo, or iodo andmore preferably X⁴ is bromo.

In the sulfide-forming step of the present reaction, it is preferredthat diphenylmethane compound 11 be contacted with the source of sulfurto form the intermediate thiolate anion 44 before being contacted withthe substituted propionaldehyde compound 12.

In the sulfide-forming step of the present inventive method, thecontacting of the source of sulfur with compound 11 can be done at anyconvenient temperature. Preferably the contacting is performed at atemperature in the range of about 0° C. to about 150° C., morepreferably about 0° C. to about 100° C., still more preferably about 10°C. to about 75° C., still more preferably about 20° C. to about 50° C.,and more preferably yet around 25° C. to about 45° C. It is helpful toallow the source of sulfur, for example sodium sulfide, to contactcompound 11 for a period of reaction time before adding substitutedpropionaldehyde compound 12 to the mixture. Appropriately, the reactiontime can be about 5 minutes to about ten hours, preferably about 10minutes to about 7 hours, more preferably about 20 minutes to about 5hours, and more preferably still about 30 minutes to about 3 hours.

Optionally, anion 44 can be quenched, for example with water or with anacid, to form thiol compound 45. Thiol 45 can be isolated, stored,transported, or kept in a solution until used. When ready to use thiol45 to prepare compound 10, thiol 45 can be treated with a suitable basesuch as a metal alkoxide, a metal hydride, an alkyl metal complex, orother base to form anion 44. Suitable bases include, for example, analkali metal alkoxide such as sodium methoxide, lithium methoxide,sodium ethoxide, lithium ethoxide, and potassium t-butoxide. Usefulmetal hydrides include sodium hydride and calcium hydride.

However, it is preferred not to quench anion 44 or to isolate thiolcompound 45. Anion 44 is sufficiently stable to store or transportwithout quenching. Alternatively, the addition of the source of sulfurand the reaction with the substituted propionaldehyde compound 12 can beperformed in one reaction vessel or in one reaction mixture withoutisolation of intermediate structures.

Alternatively, the sulfide-forming step can be performed following thereaction of Eq. 8a, wherein diphenylmethane compound 11 is contactedunder coupling conditions described above with a thiopropyl compound 12bto form sulfide 10a. In Eq. 8a, R¹, R², R⁶, R²⁷, and X³ are as definedabove and R²⁸ is H or a labile thiol protecting group such as an acylgroup, preferably an acetyl group.

The reaction of Eq. 8a can conveniently be performed in the presence ofa base. Useful bases include an alkali metal base or an alkaline earthmetal base. Useful alkali metal bases include alkali metal hydroxidessuch as sodium hydroxide or potassium hydroxide. Conveniently, thereaction of Eq. 8a can be performed in the presence of a solvent,preferably an aprotic solvent, and more preferably a polar aproticsolvent. A preferred solvent for the reaction of Eq. 8a is DMSO.

Conveniently, the sulfide-forming step of Eq. 8a can be performed in thepresence of a solvent. Useful solvents include polar aprotic solvents.Without limitation, useful polar aprotic solvents includeN,N-dimethylacetamide (DMAC), dimethylsulfoxide (DMSO),dimethylformamide (DMF), and N-methylpyrrolidone (NMP). Preferably thesolvent is DMAC.

Where R²⁷ of Eq. 8a is a protected aldehyde group such as an acetalgroup, compound 10a can be further reacted to deprotect the protectedacetal group, if desired. Alternatively, compound 10a can be directlyoxidized under sulfide oxidizing conditions described herein to formsulfone compound 10c. If desired, compound 10c can be treated underreductive alkylation conditions described herein to form a dimethylaminoaldehyde compound 10b as shown in Eq. 8b.

FIG. 1 shows an overall process by which substituted propionaldehydecompound 12 can be prepared. Compound 12 can be made, for example, byreacting a diol compound having the structure of Formula 37 in thepresence of a carbonyl compound having the structure of Formula 38 and asource of X⁴ to form an acid ester having the structure of Formula 36.X⁶ can be hydroxy, halo, or —OC(O)R¹⁸; preferably hydroxy or halo. WhenX⁶ is halo, preferably it is chloro, bromo, or iodo; more preferablychloro. Alternatively X⁶ can be hydroxy. When X⁶ is hydroxy, thereaction of compound 37 with the carbonyl compound 38 is advantageouslyperformed in the presence of a strong acid, preferably a strong mineralacid. Useful strong acids include HCl, HBr, HI, sulfuric acid, or asulfonic acid. Useful sulfonic acids include methanesulfonic acid,trifluoromethanesulfonic acid, p-toluenesulfonic acid, andbenzenesulfonic acid. Preferably the strong acid is HBr. R¹⁰ and R¹⁸independently can be C₁ to about C₂₀ hydrocarbyl; preferably C₁ to aboutC₁₀ alkyl; more preferably C₁ to about C₅ alkyl; more preferably stillmethyl, ethyl, or isopropyl; and still more preferably methyl. R¹, R²,and X⁴, are as defined above. The source of X⁴ can be, for example, asource of halide. The source of halide can be any source in which thehalide can nucleophilically displace an acyloxy group such as —OC(O)R¹⁰.For example, the source of halide can advantageously be the strong acidwhen the strong acid is HCl, HBr, or HI. Preferably the source of halideis a source of bromide such as NaBr, LiBr, or HBr. When the source ofbromide is NaBr or LiBr, it is advantageous to perform the reaction inthe presence of an acid catalyst. Preferably the source of halide is HBror HI, more preferably HBr. Advantageously, the reaction to formcompound 36 can be performed over a wide range of temperatures.Preferably the reaction is performed from about 50° C. to about 175° C.,more preferably about 65° C. to about 150° C., still more preferablyabout 70° C. to about 130° C.

Acid ester 36 can be solvolyzed to form a substituted propanol compoundhaving the structure of Formula 35. The solvolysis reaction can beperformed under conditions known in the art for the solvolysis ofcarboxylic acid esters without displacing X⁴. It is convenient toperform the solvolysis in the presence of an acid catalyst. A usefulacid catalyst can be a mineral acid or an organic acid. When the acidcatalyst is a mineral acid, it can be for example a hydrogen halideacid, sulfuric acid, or a sulfonic acid. Useful sulfonic acids includemethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, andtrifluoromethanesulfonic acid. Useful hydrogen halide acids includehydrochloric acid, hydrobromic acid, and hydroiodic acid; preferablyhydrobromic acid. The solvolysis can be performed in the presence of asolvent. Preferably the solvent is a C₁ to about C₁₀ alcohol solvent;more preferably a C₁ to about C₅ alcohol solvent; still more preferablymethanol, ethanol, propanol, or 2-propanol; and more preferably stillethanol.

The reactions to form compounds 36 and 35 can be performed separatelywith individual isolation of the products. Alternatively, the reactionscan be performed in a single reaction vessel or in a single reactionmedium without isolation of compound 36.

The substituted propanol compound 35 can be oxidized to form thesubstituted propionaldehyde compound 12. This can be achieved bycontacting compound 35 with an oxidizing agent. Oxidation conditionsshould be appropriate to those in which an alcohol group is oxidized inthe presence of X⁴. For example, the oxidizing conditions can comprise amild oxidizing agent such as sulfur trioxide-pyridine complex. Otheruseful oxidizing conditions include, for example, contacting 35 withoxalyl chloride and triethylamine in the presence of a reactant such asDMSO. Another example of useful oxidizing conditions comprise contacting35 with sodium hypochlorite in the presence of2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO). When theoxidizing agent is sulfur trioxide-pyridine complex, the oxidation canadvantageously be performed at a temperature from about 10° C. to about100° C.; preferably about 20° C. to about 75° C.; more preferably about20° C. to about 50° C. The oxidation can be performed in the presence ofa solvent. Useful solvents include for example a sulfoxide such as DMSO;or a chlorinated solvent such as methylene chloride, chloroform, orcarbon tetrachloride. When the oxidizing agent is sulfurtrioxide-pyridine complex, the complex can be added to the reactionmixture either as a slurry in a solvent or, preferably, as a solid addedover a period of time (for example about 1 to about 15 hours).

In one preferred embodiment of the preparation of compound 12, both R¹and R² are butyl. In an alternative preferred embodiment, one of R¹ andR² is ethyl and the other of R¹ and R² is butyl. When one of R¹ and R²is ethyl and the other of R¹ and R² is butyl, compound 12 can have an Rabsolute configuration about the quaternary carbon atom. Alternatively,compound 12 can have an S absolute configuration about the quaternarycarbon atom.

The reactions described herein that are useful for the preparation ofcompound 12 can be performed individually or in combination. FIG. 2shows a preferred process by which 2,2-dibutyl-3-bromopropionaldehydecan be prepared using the methods of the present invention.

One embodiment of the present invention is shown in Eq. 8c whereincompound 12b can have the structure of compound 12d. Eq. 8c is exemplaryof a large variety of methods by which thioacyl acetal compounds usefulin the present invention can be made in which the acyl group and theacetal group can independently vary widely in structure. In Eq. 8cbromoaldehyde compound 53 is treated with potassium thioacetate to formthioacetyl aldehyde compound 12c. Compound 12c is treated with atrialkyl formate such as triethylformate in the presence of an acidcatalyst such as a sulfonic acid catalyst (preferably toluenesulfonicacid) to form compound 12d, wherein Et is ethyl. The acetal-forming stepcan be performed, if desired, in the presence of a solvent, for examplean alcohol solvent. When the acetal formed is an ethyl acetal, thesolvent can conveniently be ethanol.

FIG, 1 a shows a representative overall process by which nitro sulfideacetal compound 67 (10a wherein R¹ and R² are both butyl and R²⁷ is adiethylacetal group) can be prepared and by which compound 67 can beused to produce compound 29.

Compound 12b can, if desired, be prepared by a number of other methods.For example, acrolein compound 77 can be contacted with thioacylcompound 78 to form acylthiomethyl aldehyde compound 79 as shown in Eq.8d. In Eq. 8d, R²⁹ can be C₁ to about C₂₀ hydrocarbyl, preferably C₁ toabout C₁₀ hydrocarbyl, more preferably C₁ to about C₅ hydrocarbyl, andstill more preferably ethyl or butyl. R³⁰ can be C₁ to about C₂₀hydrocarbyl, preferably C₁ to about C₁₀ hydrocarbyl, more preferably C₁to about C₅ hydrocarbyl, and still more preferably methyl. Preferablythe reaction of Eq. 8d is performed in the presence of a base catalystsuch as an amine catalyst. For example the amine catalyst can be analkylamine such as trialkylamine.

Compound 79 can be contacted with compound 20 to form acylthiomethylalkene aldehyde compound 80 as shown in Eq. 8e. The reaction in Eq. 8eis preferably performed in the presence of an acid catalyst, preferablya sulfur acid catalyst such as sulfuric acid or a sulfonic acid. Forexample the acid catalyst can be p-toluenesulfonic acid, benzenesulfonicacid, methanesulfonic acid, or trifluoromethanesulfonic acid. Thereaction can conveniently be carried out under heating conditions, forexample at a temperature of about 50° C. to about 150° C., preferablyabout 75° C. to about 125° C., more preferably about 100° C. to about115° C.

Compound 80 can be derivatized under acetal-forming conditions to formunsaturated acetal compound 81. In compound 81, R³¹ and R³²independently can be C₁ to about C₂₀ alkoxy or, together with the carbonatom to which they are attached can form a cyclic acetal. Where R³¹ andR³² are alkoxy, preferably they are C₁ to about C₁₀ alkoxy, morepreferably C₁ to about C₅ alkoxy, more preferably still methyl or ethyl,and still more preferably ethyl. Where R³¹ and R³² together form acyclic acetal, preferably they form an ethylene glycol acetal or a1,3-propanediol acetal, more preferably an ethylene glycol acetal. Forexample, compound 80 can be contacted with an alcohol or a mixture ofalcohols in the presence of a catalyst such as an acid catalyst.Alternatively, compound 80 can be treated with an orthoformate such astriethyl orthoformate or trimethyl orthoformate to form the acetal.

Compound 81 can be reduced to produce thiomethyl acetal compound 82. Itwill be apparent to one of skill in the art given the present disclosurethat compound 82 can be used in place of compound 12b in the reaction ofEq. 8a to form sulfide 10a. Reduction conditions to convert compound 81to compound 82 can vary widely. For example, compound 81 can be treatedwith a hydrazide such as p-toluenesulfonyl hydrazide in the presence ofan amine such as piperidine to form compound 82.

Once the nitro sulfide aldehyde compound 10 is formed in thesulfide-forming step, 10 can be isolated by methods known in the art orit can be oxidized to form nitro sulfone aldehyde compound 9 by methodsdescribed above. While intermediate compounds can optionally beisolated, stored, or transported, it is convenient to perform thesulfide-forming step and the oxidation step in one reaction vesselwithout isolation of intermediate structures.

The method of the present invention can further comprise a reductionstep in which a substituted benzophenone compound 13

is reduced to form the substituted diphenyl methane compound 11 whereinR⁶ and X³ are defined above. The reduction step is shown in Eq. 9. Forexample, the reduction step can be carried out by contacting compound 13with trifluoromethanesulfonic acid (triflic acid) and a silane such astriethyl silane. It is useful to perform the reduction step in thepresence of a solvent, for example a strong acid solvent such astrifluoroacetic acid. When trifluoroacetic acid is used as a solvent,the triflic acid is preferably used in a catalytic amount. Particularly,it is useful to dissolve 13 in trifluoroacetic acid, add the triflicacid, and then add triethyl silane. Reaction temperature during theaddition of the triethyl silane can be controlled, if necessary, bycooling. The reaction temperature can be controlled in the range ofabout 25° C. to about 100° C., preferably about 30° C. to about 75° C.,and more preferably about 45° C. to about 50° C. Other silanes areuseful in the present reaction also, for example, polymethylhydrosiloxane (PMHS) or other trialkylsilanes.

Alternatively, the reduction of 13 to 11 can be carried out in a solventsuch as methylene chloride in the presence of triflic acid and a silanesuch as triethyl silane. When trifluoroacetic acid is absent from thereaction mixture, typically a larger-than-catalytic amount of triflicacid is required. Another method of reducing 13 to 11 will comprisetreating 13 with a Lewis acid such as aluminum chloride and a silanesuch as triethyl silane. In another alternative, the reduction can becarried out by treating 13 with sodium borohydride in the presence of acatalyst. In a further alternative, the reduction can be carried out bytreating 13 with sulfuric acid in the presence of a noble metal catalystsuch as a palladium catalyst, preferably Pd/C. In a still furtheralternative, 13 can be reduced to the corresponding alcohol, for examplewith a borohydride such as sodium borohydride. The resulting alcohol canbe treated, for example, with sodium borohydride and a silane such astriethylsilane. The alcohol can be reduced to 11 by other means, forexample treating the alcohol with a sulfonating reagent such asmethanesulfonyl chloride or toluenesulfonyl chloride and then treatingthe resulting sulfonic acid ester with sodium borohydride.

The method of the present invention can also further comprise anacylation step in which a protected phenol compound having the structureof Formula 14

is treated with a substituted benzoyl compound having the structure ofFormula 15

under acylation conditions to produce a substituted benzophenonecompound having the structure of Formula 13 wherein R⁶ and X³ aredefined above; X⁵ can be hydroxy, halo, or —OR¹⁴; and R¹⁴ can be an acylgroup. This overall acylation step is shown in Eq. 10.

The acylation conditions can comprise Friedel-Crafts acylationconditions. For example the acylation conditions can further comprise aLewis acid. Useful Lewis acids include aluminum-containing Lewis acidssuch as an aluminum trihalide; boron-containing Lewis acids such asboron trifluoride, boron trifluoride etherate, or boron trichloride;tin-containing Lewis acids such as SnCl₄; halogen-containing Lewis acidssuch as HF; iron-containing Lewis acids such as FeCl₃;antimony-containing Lewis acids such as SbF₅; and zinc-containing Lewisacids such as ZnI₂ or ZnCl₂. When the Lewis acid is an aluminumtrihalide, preferably it is AlCl₃ or AlBr₃, more preferably AlCl₃.Alternatively, the Lewis acid can be supported on a solid support suchas a clay. For example, the Lewis acid can comprise an FeCl₃ on claycomposition such as Envirocat.

Alternatively, the acylation can be run in the presence of a strongprotic acid such as sulfuric acid; a phosphoric acid, for exampleo-phosphoric acid or polyphosphoric acid (PPA); or a sulfonic acid, forexample p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonicacid, or trifluoromethanesulfonic acid.

X⁵ can be hydroxy, halo, or —OR^(14.) For example, X⁵ can be hydroxy,bromo, iodo, or —OR¹⁴.

When X⁵ is halo, preferably it is chloro, bromo, or iodo. In one usefulembodiment X⁵ is chloro. In another useful embodiment X⁵ is bromo oriodo, preferably bromo. When X⁵ is halo, it is preferred that theacylation conditions further comprise a Lewis acid as described above,for example an aluminum trihalide. Useful aluminum trihalides includealuminum tribromide and aluminum trichloride, preferably aluminumtrichloride.

When X⁵ is hydroxy, it is preferred that the acylation conditionsfurther comprise a strong protic acid. Some useful strong protic acidsinclude sulfuric acid, a sulfonic acid, or a phosphorus oxy acid. Usefulphosphorus oxy acids include orthophosphoric acid (commonly known asphosphoric acid, H₃PO₄), pyrophosphoric acid (H₄P₂O₇), or polyphosphoricacid (PPA). Preferably the phosphorus oxy acid is phosphoric acid orpolyphosphoric acid, preferably polyphosphoric acid. Combinations ofphosphorus oxy acids are also useful in the present invention. Thephosphorus oxy acid can be added as the acid per se or it can begenerated in situ, for example by the hydrolysis of a phosphorus halidecompound such as PCl₅ or by the hydrolysis of a phosphorus oxidecompound such as P₂O₅.

When R¹⁴ is —OR¹⁴ and R¹⁴ is an acyl group, compound 15 is a carboxylicacid anhydride. The acid anhydride can have a symmetrical structure;i.e., X⁵ can have the structure of Formula 46. Alternatively, the acidanhydride can be a mixed anhydride. For example R¹⁴ can be a formylgroup, an acetyl group, a benzoyl group or any other convenient acylgroup.

When X⁵ is —OR¹⁴, it is preferred that the acylation conditions furthercomprise a Lewis acid as described above, for example an aluminumtrihalide.

Useful aluminum trihalides include aluminum tribromide and aluminumtrichloride, preferably aluminum trichloride.

An alternative method for the preparation of compound 13 is shown in Eq.11. When X⁵ of compound 15 is halo or —OR¹⁴, compound 15 can be treatedwith compound aryl metal complex 56 wherein L is a metal-containingmoiety and R⁶ is as defined above. The group L can be, for example,MgX⁶, Na, or Li, wherein X⁶ is a halogen. When L is MgX⁶ (in otherwords, when 56 is a Grignard reagent), X is preferably Br, Cl, or I;more preferably Br or Cl.

The present inventive method can further comprise one or more stepswherein a nitro alkenyl aldehyde compound having the structure ofFormula 16 is reduced and reductively alkylated to form an amino alkylaldehyde compound having the structure of Formula 17 (Eq. 12) wherein R¹and R⁶ are defined above, R⁷ is H or C₁ to about C₁₇ hydrocarbyl, and tis 0, 1, or 2. Preferably R⁷ is a C₁ to about C₁₀ alkyl group, morepreferably a C₁ to about C₅ alkyl group, still more preferably C₁ toabout C₃ alkyl group, and more preferably still methyl. Preferably t is2.

The reduction and reductive alkylation of compound 16 to compound 17 canbe performed in a single step or it can be performed in discrete steps.For example, the reduction of the double bond can be done at the sametime as the reductive alkylation of the nitro group. Alternatively, thealiphatic C—C double bond in compound 16 can be reduced to a single bondin a step that is discrete from the reductive alkylation of the nitrogroup to the dimethylamino group. As another alternative, in a firststep the nitro group and the alkene double bond of compound 16 can bereduced to an amino group and to an alkyl group, respectively, and thenthe amino group can be methylated. The reduction of the nitro group andthe alkene double bond will be readily performed with the use of ahydrogenation catalyst as is known in the art. Such a reduction will runin the presence of H₂. The methylation of the reduced amino group can beperformed with essentially any methylating agent as is known in the art,for example a methyl halide such as methyl iodide, methyl bromide, ormethyl chloride. Another useful methylating agent is dimethyl sulfate.

The conditions under which compound 16 is reduced and reductivelyalkylated can include, for example, contacting 16 with a source offormaldehyde and a source of H₂ in the presence of a catalyst. Theconversion is preferably performed at elevated H₂ pressure. It is usefulto perform the conversion at H₂ pressures ranging from about 100 toabout 700,000 kPa, preferably from about 200 to about 300,000 kPa, morepreferably from about 300 to about 100,000 kPa, still more preferablyfrom about 350 to about 10,000 kpa, and more preferably still from about400 to about 1000 kPa.

The source of formaldehyde can be essentially any source that producesthe equivalent of CH₂O. For example, the source of formaldehyde can beformalin, an acetal of formaldehyde such as dimethoxymethane,paraformaldehyde, trioxane, or any polymer of CH₂O. Conveniently thesource of formaldehyde can be formalin, and preferably about 35% toabout 37% formalin.

The catalyst for the reduction and reductive alkylation can be either aheterogeneous catalyst or a homogeneous catalyst. Preferably thecatalyst is a metal, for example the catalyst can be a noble metalcatalyst. Useful noble metal catalysts include Pt, Pd, Ru, and Rh.Preferably the noble metal catalyst is a Pd catalyst. The noble metalcatalyst can be used either in a homogeneous or in a heterogeneous form.When used in a heterogeneous form, the catalyst can be used, forexample, as the metal per se or on a solid support such as carbon or analuminum oxide. In a particularly preferred embodiment, the catalystcomprises palladium and more preferably Pd on carbon. In anotherembodiment the catalyst comprises a nickel catalyst such as ahigh-surface area nickel catalyst. A useful high-surface area nickelcatalyst is Raney nickel.

An acid can be present in the reaction mixture during the reduction andreductive alkylation. Preferably the acid is a strong acid and morepreferably a strong mineral acid. For example, the acid can be sulfuricacid.

A solvent can conveniently be present in the reaction mixture during thereduction and reductive alkylation. Useful solvents include an alcohol,an ether, a carboxylic acid, an aromatic solvent, an alkane, acycloalkane, or water. Preferably the solvent is an alcohol solvent suchas a C₁ to about C₁₀ alcohol; more preferably a C₁ to about C₅ alcohol;and more preferably still methanol, ethanol, propanol, or isopropylalcohol. In a particularly preferred embodiment, the solvent is ethanol.

The reduction and reductive alkylation reaction can be run at anyconvenient temperature, for example from about 0° C. to about 200° C.,preferably from about 10° C. to about 150° C., more preferably fromabout 15° C. to about 100° C., still more preferably from about 20° C.to about 75° C., more preferably still from about 25° C. to about 60°C., and more preferably yet from about 30° C. to about 40° C.

Alternatively, the conversion of 16 into 17 can be performed in discretesteps. For example, in a first step the nitro group and the alkenedouble bond of compound 16 can be reduced to an amino group and to analkyl group, respectively. In a second step the amino group can bemethylated. The reduction of the nitro group and the alkene double bondcan be readily performed with the use of a hydrogenation catalyst as isknown in the art. Such a reduction will run in the presence of H₂. Themethylation of the reduced amino group can be performed with essentiallyany methylating agent as is known in the art, for example a methylhalide such as methyl iodide, methyl bromide, or methyl chloride.Another useful methylating agent is dimethyl sulfate.

An alternative route to compound 17 is shown in Eq. 13, wherein u ofcompound 16a is 0 or 1 (in other words, when compound 16a is a sulfideor a sulfoxide compound). In the instant route, compound 16a can bereduced by methods described herein (for example by contacting 16a withH₂ and a hydrogenation catalyst such as Pd/C) to form compound 57wherein u is 0 or 1, R¹, R⁶, and R⁷ are as defined above, and R¹⁹ can be—NH₂, —NHOH, or —NO₂. Compound 57 can be oxidized (for example bymethods described herein for the conversion of sulfides or sulfoxides tosulfones) to compound 58 wherein R¹, R⁶, and R⁷ are as defined above,and R²⁰ can be —NH₂, —NHOH, or —NO₂. Compound 58 can be alkylated orreductively alkylated by methods described herein to form compound 17wherein t is 2.

the method of the present invention can further comprise a thermolysisstep wherein an acetal compound having the structure of Formula 18

is thermolyzed to form the nitro alkenyl aldehyde compound 16, whereinR¹, R⁶, and t are defined above; R⁷ can be H or C₁ to about C₁₇hydrocarbyl; and R¹³ can be H or C₁ to about C₂₀ hydrocarbyl. Thethermolysis step is shown in Eq. 14. Preferably t is 2. Preferably R⁷ isa C₁ to about C₁₀ alkyl group, more preferably a C₁ to about C₅ alkylgroup, still more preferably C₁ to about C₃ alkyl group, and morepreferably still methyl. R¹³ is preferably a C₁ to about C₁₀hydrocarbylgroup, more preferably a C₁ to about C₁₀ alkenyl group, still morepreferably a C₁ to about C₅ alkenyl group, and more preferably still aC₁ to about C₄ alkenyl group. In one preferred embodiment, R¹³ is agroup having the structure of Formula 43 wherein R⁷ is as defined above.Preferably R¹³ is 1-buten-3-yl.

The thermolysis reaction can advantageously be performed in the presenceof a base. Useful bases include without limitation a metal hydride, ametal hydroxide, a metal carbonate, or a metal bicarbonate. Preferablythe base is a metal hydride such as calcium hydride, lithium hydride,sodium hydride, or potassium hydride. More preferably the base iscalcium hydride. Other useful bases include sodium hydroxide, potassiumhydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate,or sodium bicarbonate. The thermolysis reaction can be run, for example,by contacting compound 18 with the base over a period of time,preferably under essentially anhydrous conditions. Surprisingly, thepresence of a soluble base such as triethylamine or pyridine during theconversion of 18a to 47 can be advantageously used to slow the reactionrate relative to reaction conditions in which the soluble base isabsent. The thermolysis can be run in the presence of a solvent.Essentially any solvent that is unreactive under the thermolysisreaction conditions is useful. Aprotic solvents are especially usefuland aromatic solvents are preferred, such as benzene, toluene, o-xylene,m-xylene, p-xylene, mesitylene, and naphthalene. Especially preferredsolvents include toluene, o-xylene, m-xylene, p-xylene, or mesitylene;more preferably toluene, o-xylene, m-xylene, or p-xylene; and morepreferably still toluene or o-xylene. Other useful solvents include anether such as tetrahydrofuran, diethyl ether, or diphenyl ether; anester such as ethyl acetate; an alcohol such as ethanol or t-butylalcohol; or a ketone such as acetone or benzophenone.

In another embodiment, the thermolysis can be performed neat, i.e., inthe absence of a solvent. For example, compound 18 can be heated neat toproduce compound 16a. When compound 18 is heated neat, the thermolysiscan be run, if desired, at subambient pressure. For example, thethermolysis can be run at a pressure at which elimination productsproduced by the thermolysis boil away. Operating the reaction under suchconditions will aid in driving the thermolysis reaction to completion.Advantageously, the reaction pressure during the thermolysis can be lessthan about 760 mmHg (101 kPa), preferably less than about 500 mmHg (66.6kPa), more preferably less than about 250 mmHg (33.3 kPa), morepreferably still less than about 100 mmHg (13.3 kPa), still morepreferably less than about 50 mmHg (6.7 kPa), and more preferably yetless than about 10 mmHg (1.3 kPa).

The thermolysis can be run over a wide range of temperatures. Forexample the thermolysis can be run at a temperature in the range ofabout 10° C. to about 250° C., preferably about 50° C. to about 200° C.,more preferably about 75° C. to about 175° C. and more preferably stillabout 100° C. to about 150° C. Conveniently the thermolysis can be runin a refluxing solvent, for example refluxing o-xylene. Alternatively,the thermolysis can be performed at pressures above ambient pressure,thereby allowing the reaction to proceed at temperatures above theambient-pressure boiling point of the solvent.

The thermolysis reaction is preferably performed under dry oressentially anhydrous conditions and in the absence of acid to preventreverse reaction and byproduct formation.

Without intending to limit the scope of the present invention, thethermolysis reaction to form compound 16 is believed to proceed by theintermediacy of an enol ether compound. For example, bis-butenyl acetalcompound 18a is thought to eliminate a molecule of 3-buten-2-ol to formenol ether 47 (a pre-Claisen intermediate) as shown in Eq. 15. Compound47 is then believed to undergo a [3,3]-sigmatropic shift (also known asa Claisen rearrangement) to form butenyl sulfone aldehyde compound 31 asshown in Eq. 16. Although compound 47 is shown herein as having aE-configuration across the double bond between the methanesulfonylmoiety and the alkoxy moiety, it is also possible that this compound canform in the Z-configuration.

The conversion of 18a to 31 can be carried out for example by heating at145° C. a toluene or o-xylene solution of a mixture comprising 18a or amixture of 18a and 47, preferably in the presence of calcium hydride.Alternatively, the conversion of 18a to 31 can be achieved by filteringcrude 18a through an acidic medium such as silica gel or a basic mediumsuch as basic alumna prior to heating.

The addition of soluble bases such as triethylamine or pyridine duringthe conversion of 18a to 47 can be used, if desired, to decrease thethermolysis reaction rate relative to the situation in which the solublebase is absent.

Compound 18 can be prepared by a step in which a monoalkyl aldehydecompound having the structure of Formula 19 is reacted with an allylalcohol compound having the structure of Formula 20 in the presence of ahydroxylated solvent having the structure HOR¹³ to form an acetalcompound having the structure of Formula 18, wherein R¹, R⁶, R⁷, R¹³,and t are as defined above. Preferably t is 2. In a preferredembodiment, R¹³ has the structure of Formula 43. For example, thisembodiment can be realized if the allyl alcohol compound 20 itself isused as a hydroxylated solvent, preponderating over another hydroxylatedsolvent or essentially in the absence of another hydroxylated solvent.The conversion of compound 19 into compound 18 is shown in Eq. 17.

Acetal compound 18 can be prepared by numerous methods employing variousconditions known in the art. The reaction to form the acetal ispreferably performed in the presence of an acid catalyst. The catalystcan be, for example, a strong acid such as sulfuric acid, hydrochloricacid, phosphorous acid, phosphoric acid, trifluoroacetic acid, or asulfonic acid. Useful sulfonic acids include methanesulfonic acid,toluenesulfonic acid, benzenesulfonic acid, and trifluoromethanesulfonicacid. However, organic acids and acidic heterogeneous catalysts alsowork to mediate this reaction, for example pyridiniump-toluenesulfonate, acetic acid, propionic acid, Amberlyst 15, acidiczeolites, acidic clay, Pd(PhCN)₂Cl₂, and AlCl(CH₂CH₃)₂. Virtually anyBronsted-Lowry or Lewis acid can be employed as a catalyst. Theacetal-forming reaction can if desired be performed in the presence of asolvent. Useful solvents include chlorinated solvents such as methylenechloride, chloroform, or carbon tetrachloride; aromatic solvents such asbenzene, toluene, o-xylene, m-xylene, p-xylene, mesitylene, ortrifluoromethylbenzene; aprotic solvents including CH₃CN, ethyl acetate,isopropyl acetate, butyl acetate, tetrahydrofuran, methyl isobutylketone, 1,4-dioxane; or alcohols such as 3-buten-2-ol. The reaction canbe run at essentially any convenient temperature that does not lead tosignificant degradation of starting material or product. For example,the temperature can be in the range of about 0° C. to about 200° C.;preferably about 20° C. to about 150° C.; more preferably about 30° C.to about 135° C. The reaction can be performed in a refluxing solventsuch as refluxing methylene chloride. The conversion can conveniently beperformed during azeotropic removal (distillation) of the solvent andwater. For example, the conversion can be achieved during azeotropicremoval of toluene (about 105° C. to about 115° C.) or of xylene (about125° C. to about 135° C.).

Optionally, removal of water during the reaction or concomitant with thereaction can advantageously be used to increase conversion or yield.Without meaning to limit the scope of the invention, it is believed thatremoval of water drives the acetal-forming reaction toward completion.For example, process apparatus similar to a Dean-Stark trap orazeotropic distillation equipment can be used to remove water. Othermethods such as molecular sieve (zeolites), isopropenyl acetate, andtrimethyl orthoformate can also be used.

Advantageously, the conversion of 18a to 47 and the conversion of 47 to31 can be carried out sequentially or simultaneously in a singlereaction vessel or in a single reaction mixture without isolation. Tofurther advantage, the preparation of the acetal 18 from aldehyde 19,the conversion of 18 to the corresponding enol ether intermediate, andthe conversion of the enol ether intermediate to 31 can all be carriedout in a single reaction vessel or reaction mixture. For example,2-(((4-methylphenyl)sulfonyl)methyl)hexanal can be heated in a solventsuch as toluene in the presence of 3-buten-2-ol and p-toluenesulfonicacid with removal of water (e.g., with a Dean-Stark trap) to produce2-butyl-2-(((4-methylphenyl)sulfonyl)methyl)hex-4-enal.

This useful and surprising overall method for preparing a2-alkenyl-2,2-disubstituted aldehyde 49 has general applicability. Thegeneral method can be employed in the conversion of a3-sulfur-propionaldehyde compound 48 to the 3-sulfur-propionaldehydeolefin compound 49 as shown in Eq. 18. Conditions described above forthe conversion of compound 19 to compound 16 are useful in the broadreaction of Eq. 18.

In the reaction of Eq. 18:

R¹⁵ is selected from the group consisting of H, alkyl, alkenyl, alkynyl,aryl, alkylaryl, arylalkylaryl, and acyl, wherein alkyl, alkenyl,alkynyl, aryl, alkylaryl, arylalkylaryl, and acyl optionally aresubstituted with at least one R²² group;

R¹⁶, R¹⁷, R^(21a), and R^(21b) are independently selected from the groupconsisting of H and hydrocarbyl;

R²² is selected from the group consisting of H, —NO₂, amino, C₁ to aboutC₁₀ alkylamino, di(C₁ to about C₁₀)alkylamino, C₁ to about C₁₀alkylthio, hydroxy, C₁ to about C₁₀ alkoxy, cyanato, isocyanato,halogen, OR⁶, SR⁶, SR⁶R^(6a), and NR⁶R^(6a);

R⁶ and R^(6a) independently are selected from the group consisting of Hand a protecting group; and

q is 0, 1,or 2.

Preferably R¹⁵ is selected from the group consisting of aryl, alkylaryl,and arylalkylaryl. More preferably R¹⁵ is selected from the groupconsisting of aryl, alkylaryl, and arylalkylaryl, wherein aryl,alkylaryl, and arylalkylaryl are optionally substituted with at leastone R²² group. More preferably still, R¹⁵ is arylalkylaryl optionallysubstituted with at least one R²² group, and more preferably still R¹⁵is 2-(phenylmethyl)phenyl optionally substituted with at least one R²²group. R¹⁵ therefore can include without limitation any of the moietiesshown in Table A, wherein R⁶ is as defined above.

TABLE A Number Structure 59a

59b

59c

59d

59e

59f

59g

59h

59i

59j

When R¹⁶ is hydrocarbyl, it can be unsubstituted hydrocarbyl, forexample C₁ to about C₁₀ alkyl and preferably C₁ to about C₅ alkyl. Morepreferably, when R¹⁶ is unsubstituted hydrocarbyl, it is ethyl or butyl.

In the reaction of Eq. 18, R¹⁷ is preferably hydrocarbyl, morepreferably C₁ to about C₁₀ alkyl, still more preferably C₁ to about C₅alkyl, and more preferably still methyl.

R^(21a) and R^(21b) preferably independently are selected from the groupconsisting of H, C₁ to about C₁₀ alkyl, C₂ to about C₁₀ alkenyl, and C₂to about C₁₀ alkynyl; more preferably R^(21a) and R^(21b) are both H.

Preferably q is 2 in the reaction of Eq. 18.

The reaction of Eq. 18 can be run at essentially any convenienttemperature that does not lead to significant degradation of startingmaterial or product. For example, the temperature can be in the range ofabout 0° C. to about 200° C.; preferably about 20° C. to about 150° C.;more preferably about 30° C. to about 135° C.; and more preferably stillabout 30° C. to about 100° C.

Compound 48 can be prepared by any of a variety of methods. For example,48 can be prepared by the reaction of Eq. 18a wherein an acroleincompound (65) is treated with a nucleophilic organosulphur compound (66)to produce compound 48. The reaction of Eq. 18a is preferably performedin the presence of a base, preferably an amine, and more preferably analkylamine such as triethylamine. Preferably the base is present in acatalytic amount. In Eq. 18a R¹⁵, R¹⁶ R^(21a) R^(21b) and q are asdefined above.

The monoalkyl sulfone aldehyde compound 19 can be prepared in asulfone-forming reaction by treating a substituted diphenyl methanecompound 11 under sulfination conditions and coupling it with a2-substituted acrolein compound having the structure of Formula 21 toform compound 19. The sulfone-forming reaction is shown in Eq. 19.

The sulfination conditions can comprise, for example, treating compound11 with a source of a metal sulfide such as Na₂S, Na₂S₂, or Li₂S,preferably Na₂S₂. The sulfination conditions can further comprise water.After treating with the metal sulfide, the substrate can be oxidized toform sulfinic acid 51 or a salt thereof (Eq. 20). A variety of oxidizingconditions can be used to effect this oxidation. For example, a usefuloxidizing agent includes a source of hydrogen peroxide.

During the addition of the metal sulfide, the temperature of the mixturecan vary over a wide range. It is useful to react compound 11 with themetal sulfide at a temperature of about 25° C. to about 125° C.,preferably about 40° C. to about 100° C., and more preferably about 50°C. to about 80° C. This reaction can be run in the presence of asolvent. Essentially any solvent into which hydrogen peroxide candissolve is useful for the present reaction. Useful solvents include analcohol such as a C₁ to about C₁₀ alcohol; preferably a C₁ to about C₅alcohol; more preferably methanol, ethanol, propanol, or 2-propanol;still more preferably ethanol. Other useful solvents include amides suchas dimethylacetamide. During the oxidation with hydrogen peroxide, thereaction is preferably maintained at less than about 30° C., morepreferably less than about 25° C., more preferably less than about 20°C. If desired, sulfinic acid compound 51 can be isolated as the acid or,preferably, as a salt.

Alternatively, 51 can be further used with or without isolation. Forexample, 51 can be treated with acrolein compound 21 to producemonoalkyl sulfone aldehyde compound 19. The reaction with compound 21can be done at essentially any convenient temperature, including ambienttemperature. The present reaction can also be run in the presence of asolvent. Useful solvents include nitriles such as acetonitrile; aromaticsolvents such as benzene, toluene, o-xylene, m-xylene, p-xylene, ormesitylene; or chlorinated solvents such as methylene chloride. In oneembodiment, the present reaction is run under biphasic conditions in thepresence of tetrabutylammonium iodide.

When R⁶ is methyl and when R¹ is 2-butylacrolein, the product of thesulfone-forming step is butyl sulfone aldehyde 32.

The reactions described herein can be run individually, for example toprepare intermediate compounds for storage, use in other reactions, orfor commerce. Alternatively two or more of the reactions can becombined. For example, an overall process for the preparation ofbenzylammonium compound 1 is shown in FIG. 3. Methods and reagentsdescribed in this disclosure can be used in the process of FIG. 3.Diphenyl methane compound 11 can, if desired, be prepared by the processshown in FIG. 4, also using methods and reagents described herein.

The methods described herein can also be combined with other reactionsin the art and still be within the scope and spirit of the presentinvention. For example, PCT Patent Application No. WO 99/32478 describesa method of preparing an enantiomerically enrichedtetrahydrobenzothiepine oxide such as compound (4R,5R)-24 (Example 9 inWO 99/32478) using an asymmetric oxidizing agent. The process of FIG. 5shows one of many ways in which an enantiomerically enrichedtetrahydrobenzothiepine oxide 24 (for example (4R,5R)-24) can be used incombination with the methods of the present invention to prepare anenantiomerically enriched benzylammonium compound (for example (4R,5R)-1and more specifically (4R,5R)-41). The enantiomerically enrichedcompound 24 as used can be prepared as in WO 99/32478 or it can beprepared using methods disclosed hereinbelow. As used herein, asterisksin chemical structures represent chiral centers.

Other methods can alternatively be used in the process of the presentinvention to obtain an enantiomerically enriched benzylammoniumcompound. For example, one of the intermediates or products having oneor more chiral centers in FIG. 3 can be optically resolved. An opticalresolution is any technique by which an enantiomer of a compound isenriched in concentration relative to another enantiomer of thecompound. Useful methods of optical resolution includeco-crystallization with a chiral agent, for example as a salt with anoptically active counterion, i.e., crystallization of a diastereomericsalt. Another useful technique for the optical resolution of thecompounds in the present invention is to derivatize a compound havingone or more chiral centers with an optically active derivatizing agentthereby forming a diastereomeric derivative. The diastereomericderivative can then be separated into its individual diastereomers forexample by fractional crystallization or chromatography.

Another method useful for optically resolving intermediates or productsin the present process is chiral chromatography. Any of several types ofchiral chromatography can be used in the instant invention. For example,the chiral chromatographic technique can include continuouschromatography, semi-continuous chromatography, or single column (batch)chromatography. An example of continuous chromatography is simulatedmoving bed chromatography (SMB). U.S. Pat. No. 2,985,589, hereinincorporated by reference, describes the general theory of SMB. Anotherreference that describes the general theory of SMB is U.S. Pat. No.2,957,927, herein incorporated by reference. Still another referencedescribing SMB is U.S. Pat. No. 5,889,186.

Still another chiral chromatographic technique useful in the presentinvention is a semi-continuous technique such as closed-loop recyclingwith periodic intra-profile injection (CLRPIPI). CLRPIPI is described byC. M. Grill in J. Chrom. A, 796, 101-113 (1998).

Single column or batch chromatography is also useful in the presentinvention for performing the optical resolution.

In any of the chiral chromatographic techniques referenced herein, avariety of conditions can be used. Each of the techniques requires astationary phase and a mobile phase. The stationary phase can comprise achiral substrate. For example the chiral substrate can comprise asaccharide or a polysaccharide such as an amylosic, cellulosic, xylan,curdlan, dextran, or inulan saccharide or polysaccharide. The chiralsubstrate optionally can be on a solid support such as silica gel,zirconium, alumina, clay, glass, a resin, or a ceramic. The chiralsubstrate can, for example, be absorbed by the solid support, adsorbedonto the solid support, or chemically bound to the solid support.Alternatively, the stationary phase can comprise another chiralsubstrate such as a tartaric acid derivative. In another alternative,the stationary phase can comprise a derivatized silica sorbent such as aPirkle sorbent.

The chiral chromatographic technique of the present invention alsocomprises a mobile phase. Any mobile phase that is capable ofdifferentially partitioning each enantiomer between the stationary phaseand the mobile phase is useful in the present invention. For example,the mobile phase can comprise water, an alcohol, a hydrocarbon, anitrile, an ester, a chlorinated hydrocarbon, an aromatic solvent, aketone, or an ether. If the mobile phase comprises an alcohol,preferably it is a C₁ to about C₁₀ alcohol, more preferably a C₁ toabout C₈ alcohol, and more preferably a C₁ to about C₅ alcohol. If themobile phase comprises a hydrocarbon, preferably it is a C₁ to about C₂₀hydrocarbon, more preferably a C₁ to about C₁₅ hydrocarbon, and stillmore preferably a C₁ to about C₁₀ hydrocarbon. Other useful solventsinclude acetonitrile, propionitrile, ethyl acetate, methylene chloride,toluene, benzene, xylene, mesitylene, acetone, methyl t-butyl ether, ordiethyl ether. Preferably the mobile phase comprises acetonitrile,toluene, or methyl t-butyl ether. The mobile phase can also comprise amixture of solvents. A preferred mobile phase mixture comprises tolueneand methyl t-butyl ether. The mobile phase can also comprise asupercritical fluid such as supercritical CO₂. Carbon dioxide can alsobe used as a mobile phase in a subcritical state such as liquid CO₂.Supercritical or subcritical CO₂ can also be used in combination withany of the other mobile phases mentioned above.

The chiral separation can be performed at any convenient temperature,preferably about 5° C. to about 45° C., more preferably about 20° C. toabout 40° C.

The optical resolution can be performed on any convenient compound orintermediate having a chiral center in the preparation of thebenzylammonium compound. For example, the optical resolution can beperformed on any one or more of compounds 1, 2, 4, 6, 7, 8, 9, 10, 12,35, 36, or 37. In one preferred embodiment, the optical resolution isperformed on compound 7. A further preferred embodiment is one in whichcompound 7 is represented by compound 24 preferably compound syn-24.

Typically in an optical resolution, two enantiomers are partially oressentially completely separated from each other. If the goal of theseparation is to obtain an enriched sample of one desired enantiomer, itis useful to have a method of converting or recycling the otherenantiomer into the desired enantiomer or into an essentially racemicmixture of enantiomers so that further optical resolution can beperformed. Where more than one chiral center exists in a molecule, aplurality of diastereomers can exist. Similarly, diastereomers can beseparated to obtain an enriched sample of one or more desireddiastereomers. It is further useful to have a method of converting oneor more other diastereomers into the desired diastereomer(s) or into amixture of diastereomers so that further separation can be performed.

Surprisingly, it has been found that this conversion or recycle ofstereoisomers can be performed in the process of the present invention.As used herein the word “stereoisomer” includes enantiomer anddiastereomer. A method is now disclosed of treating a stereoisomer of atetrahydrobenzothiepine compound 22

wherein Formula 22 comprises a (4,5)-stereoisomer selected from thegroup consisting of a (4S,5S)-diastereomer, a (4R,5R)-diastereomer, a(4R,5S)-diastereomer, and a (4S,5R)-diastereomer, to produce a mixturecomprising the (4S,5S)-diastereomer and the (4R,5R)-diastereomer,wherein the method comprises contacting a base with a feedstockcomposition comprising the (4,5)-stereoisomer of thetetrahydrobenzothiepine compound, thereby producing a mixture ofdiastereomers of the tetrahydrobenzothiepine compound; and wherein:

R¹ and R² independently are C₁ to about C₂₀ hydrocarbyl;

R⁸ is selected from the group consisting of H, hydrocarbyl,heterocyclyl, ((hydroxyalkyl)aryl)alkyl, ((cycloalkyl)alkylaryl)alkyl,((heterocycloalkyl)alkylaryl)alkyl, ((quaternaryheterocycloalkyl)alkylaryl)alkyl, heteroaryl, quaternary heterocycle,quaternary heteroaryl, and quaternary heteroarylalkyl,

wherein hydrocarbyl, heterocycle, heteroaryl, quaternary heterocycle,quaternary heteroaryl, and quaternary heteroarylalkyl optionally haveone or more carbons replaced by a moiety selected from the groupconsisting of O, NR³, N⁺R³R⁴A⁻, S, SO, SO₂, S⁺R³A⁻, PR³, P⁺R³R⁴A⁻,P(O)R³, phenylene, carbohydrate, amino acid, peptide, and polypeptide,and

R⁸ is optionally substituted with one or more moieties selected from thegroup consisting of sulfoalkyl, quaternary heterocycle, quaternaryheteroaryl, OR³, NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³, SO₃R³, oxo,CO₂R³, CN, halogen, CONR³R⁴, SO₂OM, SO₂NR³R⁴, PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻,S⁺R³R⁴A⁻, and C(O)OM;

R³, R⁴, and R⁵ are as defined above;

R²³ and R²⁴ are independently selected from the substituentsconstituting R³ and M;

A⁻ is a pharmaceutically acceptable anion and M is a pharmaceuticallyacceptable cation;

R⁹ is selected from the group consisting of H, hydrocarbyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl,polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle,quaternary heteroaryl, OR³, NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³,SO₃R³, oxo, CO₂R³, CN, halogen, NCO, CONR³R⁴, SO₂OM, SO₂NR³R⁴,PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻, S⁺R³R⁴A⁻, and C(O)OM;

n is a number from 0 to 4;

X⁷ is S, NH, or O; and

x is 1 or 2.

Preferably the group X⁷R⁸ in compound 22 is in the 3′ or the 4′ positionof the phenyl group, more preferably the 4′ position. Preferably X⁷ isNH or O, more preferably O.

A wide variety of bases can be used to effect the conversion or recycleof stereoisomers of the present invention. For example, the base can bean alkali metal hydroxide, an alkaline earth metal hydroxide, an alkalimetal alkoxide, a metal hydride, an alkali metal amide, and an alkalimetal hydrocarbyl base. Preferably the base is an alkali metal amide, ametal hydride, or an alkali metal alkoxide. Useful alkali metal amidesinclude lithium diethylamide (LDA), lithium diisopropylamide, lithiumN-methylanilide, lithium methylamide, potassium amide, sodamide, and((CH₃)₃Si)₂NNa. Useful metal hydrides include lithium hydride, sodiumhydride, and calcium hydride. Useful alkali metal alkoxides include forexample a lithium alkoxide, a sodium alkoxide, and a potassium alkoxide;preferably a sodium alkoxide or a potassium alkoxide. The alkoxide ispreferably a C₁ to about C₁₀ alkoxide; more preferably a C₁ to about C₆alkoxide; still more preferably a C₁ to about C₅ alkoxide such as amethoxide, an ethoxide, a n-propoxide, an isopropoxide, a n-butoxide, asec-butoxide, an isobutoxide, a t-butoxide, or a t-amylate. Aparticularly useful alkoxide is potassium t-butoxide. R⁸ can be forexample H, C₁ to about C₂₀ alkyl, hydroxyalkylarylalkyl, orheterocycloalkylalkylarylalkyl. Preferably R⁸ is H, or C₁ to about C₂₀alkyl; more preferably C₁ to about C₂₀ alkyl; still more preferably C₁to about C₁₀ alkyl; and more preferably still C₁ to about C₅ alkyl. In aparticularly preferred embodiment R⁸ is methyl. R⁹ can for example be H,amino, alkylamino, alkoxy, or nitro; preferably H or alkylamino, morepreferably alkylamino, and more preferably still dimethylamino. In aparticularly preferred embodiment, R⁹ is dimethylamino and n is 1. WhenR⁹ is dimethylamino and n is 1, it is preferred that R⁹ be located atthe 7-position of the tetrahydrobenzothiepine compound structure. R¹ andR² are as defined above. In one preferred embodiment both of R¹ and R²are butyl. In another preferred embodiment one of one of R¹ and R² isethyl and the other of R¹ and R² is butyl. It is preferred that the(4,5)-stereoisomer of compound 22 is a (4S,5S) diastereomer, a (4R,5S)diastereomer, or a (4S,5R) diastereomer; more preferably a (4S,5S)diastereomer. The present conversion conditions can also comprise asolvent. Useful solvents include any solvent that is essentiallynon-reactive toward the base under the reaction conditions. Preferredsolvents include ethers such as tetrahydrofuran, diethyl ether, ordioxane; or alcohols such as a C₁ to about C₁₀ alcohol. If the solventis an alcohol, preferably it is a C₁ to about C₆ alcohol; morepreferably methanol, ethanol, propanol, isopropyl alcohol, butanol,t-butyl alcohol, or t-amyl alcohol; still more preferably ethanol,t-butyl alcohol, or t-amyl alcohol; and more preferably still t-butylalcohol. The conversion of the present invention is particularlyadvantageous when the tetrahydrobenzothiepine compound has the structureof Formula 24.

The feedstock composition used in the stereoisomeric conversion of thepresent invention can further comprise amino sulfone aldehyde compound 8wherein R¹, R², and R⁶ are as defined above.

An alternate method for the stereoisomeric conversion of the presentinvention comprises treating compound 22 under elimination conditions toproduce a dihydrobenzothiepine compound having the structure of Formula23

and oxidizing the dihydrobenzothiepine compound to produce the mixtureof stereoisomers including the (4S,5S)-diastereomer and the(4R,5R)-diastereomer. R¹, R², R⁸, R⁹, n, X⁷, and x are as defined above.The elimination conditions can comprise an acid or the conditions cancomprise a base, or the elimination conditions can occur at a neutralpH. The elimination conditions can further comprise derivatizing thediastereomer of a tetrahydrobenzothiepine compound to form atetrahydrobenzothiepine derivative having an elimination-labile group atthe 4-position, and eliminating the elimination-labile group to form thedihydrobenzothiepine compound. The elimination-labile group can be, forexample, acid labile or base labile. The elimination-labile group canalso be thermally labile. For example, it can be an acetate group or a3-buten-2-oxy group. The oxidation step can comprise an alcohol-formingstep in which the dihydrobenzothiepine compound is reacted underalcohol-forming conditions to produce a mixture of stereoisomers of thetetrahydrobenzothiepine compound. For example the alcohol-formationconditions can comprise oxymercuration-demercuration. In anotherexample, the alcohol-formation conditions can comprise Kepoxidationfollowed by reduction using conditions described in PCT PatentApplication No. WO 97/33882, herein incorporated by reference.Preferably the (4,5)-stereoisomer is selected from the group consistingof a (4S,5S) diastereomer, a (4R,5S) diastereomer, and a (4S,5R)diastereomer; more preferably a (4S,5S) diastereomer. In a particularlypreferred embodiment, the tetrahydrobenzothiepine compound has thestructure of compound 24 and the dihydrobenzothiepine compound has thestructure of compound 25.

It would be particularly useful to have a form of thetetrahydrobenzothiepine compounds that is easily handled, reproduciblein form, easily prepared, and that is nonhygroscopic. A hygroscopiccompound can absorb water, for example from the ambient atmosphere, anda sample of the compound can gain weight as more water is absorbed.Absorbance of water into a sample of a compound can also affectmeasurements of the compound, for example, infrared spectra.Hygroscopicity of a pharmaceutical compound can be problematic if thatcompound absorbs water to an extent and at such a rate that weighing andmeasurement of the compound is made difficult. Accurate weighing andmeasurement of a pharmaceutical compound is important to assure thatpatients receive an appropriate dose.

Crystal forms of the tetrahydrobenzothiepine compounds described hereinand particularly of compound 41 are now disclosed.

A first crystal form (Form I) of compound 41 or its enantiomer has amelting point or a decomposition point of about 220° C. to about 235°C., preferably about 228° C. to about 232° C., and more preferably about230° C. Form I can be prepared, for example, by crystallization ofcompound 41 or its enantiomer from a solvent that comprisesacetonitrile, methanol, or methyl t-butyl ether. Preferably, Form I canbe prepared by crystallization of compound 41 or its enantiomer from asolvent comprising methanol or methyl t-butyl ether, and more preferablyfrom a solvent comprising methanol and methyl t-butyl ether. Methods forthe preparation of Form I include those described in U.S. Pat. No.5,994,391, herein incorporated by reference, examples 1426 and 1426a.

Another crystal form (Form II) of compound 41 or its enantiomer has amelting point or a decomposition point of about 278° C. to about 285° C.Form II can be prepared, for example, by crystallization of compound 41or its enantiomer from a solvent, preferably a ketone solvent, morepreferably a ketone solvent comprising methyl ethyl ketone (MEK) oracetone. By way of example, compound 41 or its (4S,5S) enantiomer can bemixed in a solvent comprising MEK and Form II can be induced tocrystallize from that solution. Preferably, compound 41 or its (4S,5S)enantiomer is dissolved in a solvent comprising a ketone such as MEK anda quantity of water (for example about 0.5% to about 5% water by weight,preferably 1% to about 4% water by weight, and more preferably 2% toabout 4% water by weight). The crystallization can be induced, forexample, by evaporating the solvent (e.g., by distillation or byexposure to a stream of a gas such as air or nitrogen for a period oftime) or by evaporating the water (e.g. by distillation or azeotroping).Alternatively, the crystallization will be induced by other traditionalcrystallization methods such as chilling or by addition of anothersolvent or by addition of a seed crystal. As another alternative,crystallization can be induced by adding additional MEK (decreasing the% by weight of water in the crystallization solvent). Form II canconveniently be caused to precipitate from a reaction mixture in whichcompound 41 is prepared (e.g., the reaction of (4R,5R)-27 with DABCO) byrunning that reaction in a solvent comprising MEK, and preferably in asolvent comprising MEK and about 0.5% to about 5% by weight of water.The precipitation can be facilitated by distilling solvent off of thereaction mixture.

Therefore in one embodiment, the present invention provides thetetrahydrobenzothiepine compound in a useful crystalline form.Particularly, the present invention provides a crystalline form (i.e.,Form II) of a tetrahydrobenzothiepine compound wherein thetetrahydrobenzothiepine compound has the structure of Formula 71 andwherein the crystalline form has a melting point or a decompositionpoint of about 278° C. to about 285° C. Preferably, Form II has amelting point or a decomposition point of about 280° C. to about 283°C., and more preferably about 282° C.

Preferably, the compound of Formula 71 has an absolute configuration of(4R,5R) (i.e., compound A) and this is a preferred absoluteconfiguration for the compound forming the crystal structure of Form II.However, the (4S,5S) enantiomer of compound 71 can also be prepared inthe crystalline form of the present invention.

FIG. 6 shows typical X-ray powder diffraction patterns for Form I (plot(a)) and Form II (plot (b)) of compound 41. Preferably the Form IIcrystalline form has the X-ray powder diffraction pattern shown in FIG.6, plot (b). Typically, Form II has an X-ray powder diffraction patternwith peaks at about 9.2 degrees 2 theta, about 12.3 degrees 2 theta, andabout 13.9 degrees 2 theta. The Form II X-ray powder diffraction patterntypically lacks peaks at about 7.2 degrees 2 theta and at about 11.2degrees 2 theta. Table 1 shows a comparison of prominent X-ray powderdiffraction peaks for Form I and Form II.

FIG. 7 shows typical Fourier transform infrared (FTIR) spectra for FormI (plot (a)) and Form II (plot (b)) for compound 41. Preferably the FormII crystalline form has the infrared (IR) spectrum shown in FIG. 7, plot(b). Typically, Form II: has an IR spectrum with a peak at about 3245cm⁻¹ to about 3255 cm⁻¹. Preferably, Form II also has an IR peak atabout 1600 cm⁻¹. Also preferably, Form II has an IR peak at about 1288cm⁻¹. Table 2 shows a comparison of prominent FTIR peaks for Form I andForm II.

FIG. 8 shows typical solid state carbon-13 nuclear magnetic resonance(NMR) spectra for Form I (plot (a)) and Form II (plot (b)) of compound41. Preferably the Form II crystalline form has the solid statecarbon-13 NMR spectrum shown in FIG. 8, plot (b). Typically, Form II hasa solid state carbon-13 NMR spectrum with peaks at about 142.3 ppm,about 137.2 ppm, and about 125.4 ppm. Table 3 shows a comparison ofprominent solid state carbon-13 NMR peaks for Form I and Form II.

FIG. 9 shows typical differential scanning calorimetry profiles for FormI (plot (a)) and Form II (plot(b)) of compound 41.

A dry sample of the crystalline form having a melting point or adecomposition point of about 278° C. to about 285° C. (i.e., Form II)typically gains less than about 1% of its own weight when equilibratedunder 80% relative humidity (RH) air at 25° C. Such a crystalline formis essentially nonhygroscopic. For example, when a sample of Form IIcrystalline form of compound 41 or an enantiomer thereof is dried atessentially 0% RH at about 25° C. under a purge of essentially drynitrogen until the sample exhibits essentially no weight change as afunction of time, the sample gains less than 1% of its own weight whenit is then equilibrated under about 80% RH air at about 25° C. For thepresent purposes, the term “essentially 0% RH” means less than about 1%RH. The term “equilibrated” means that the change in weight of a sampleover time at a given relative humidity is less than 0.0003%((dm/dt)/m₀33 100, where m is mass in mg, m₀ is initial mass, and t istime in minutes).

The present invention also provides a crystalline form of atetrahydrobenzothiepine compound wherein the tetrahydrobenzothiepinecompound has the structure of Formula 71 wherein the crystalline form isproduced by crystallizing the tetrahydrobenzothiepine compound from asolvent comprising methyl ethyl ketone. Preferably in the crystallineform of the present invention, compound 71 has a (4R,5R) absoluteconfiguration; i.e., compound 41. Alternatively, a crystal form of thepresent invention can be prepared by crystallizing the(4S,5S)-enantiomer of compound 71 from a solvent comprising methyl ethylketone.

The present invention provides a method of preparing the crystallineform of the present invention. Particularly, the present inventionprovides a method for the preparation of a crystalline form of atetrahydrobenzothiepine compound having the structure of Formula 63

wherein the method comprises crystallizing the tetrahydrobenzothiepinecompound from a solvent comprising methyl ethyl ketone, and wherein:

R¹ and R² independently are C₁ to about C₂₀ hydrocarbyl;

R³, R⁴, and R⁵ independently are selected from the group consisting of Hand C₁ to about C₂₀ hydrocarbyl, wherein optionally one or more carbonatom of the hydrocarbyl is replaced by O, N, or S, and whereinoptionally two or more of R³, R⁴, and R⁵ taken together with the atom towhich they are attached form a cyclic structure;

R⁹ is selected from the group consisting of H, hydrocarbyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl,polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle,quaternary heteroaryl, OR³, NR³R⁴, N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³,SO₃R³, oxo, CO₂R³, CN, halogen, NCO, CONR³R⁴, SO₂OM, SO₂NR³R⁴,PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻, S⁺R³R⁴A⁻, and C(O)OM;

R²³ and R²⁴ are independently selected from the substituentsconstituting R³ and M;

n is a number from 0 to 4;

A⁻ and Q⁻ independently are pharmaceutically acceptable anions; and

M is a pharmaceutically acceptable cation.

Preferably in the method of the present invention thetetrahydrobenzothiepine compound has the structure of Formula 64, andmore preferably it has the structure of compound 41.

The present invention also provides a crystal form of compound 41 or anenantiomer thereof wherein the crystalline form is produced bycrystallizing the tetrahydrobenzothiepine compound or the enantiomerfrom a solvent comprising a ketone solvent. Preferably the ketonesolvent is methyl ethyl ketone, acetone, or methyl isobutyl ketone. Morepreferably the ketone is methyl ethyl ketone.

Another aspect of the present invention embodies a method for thepreparation of Form II (“product crystal form”) of compound 41 from FormI (“initial crystal form”) of compound 41 wherein the method comprisesapplying heat to Form I. Accordingly, the present invention provides amethod for the preparation of a Form II of a tetrahydrobenzothiepinecompound having the compound structure of Formula 41 wherein Form II hasa melting point or a decomposition point of about 278° C. to about 285°C., wherein the method comprises applying heat to Form I of thetetrahydrobenzothiepine compound wherein Form I has a melting point or adecomposition point of about 220° C. to about 235° C., thereby formingForm II of compound 41. Conveniently in the present method Form I isheated to a temperature from about 20° C. to about 150° C., preferablyabout 50° C. to about 125° C., and more preferably about 60° C. to about100° C. The method can further comprise a cooling step after the step inwhich Form I is heated. If desired, the conversion of Form I into FormII can be performed in the presence of a solvent. For example, theconversion can be performed on a slurry of Form I mixed with a solvent.The solvent can comprise essentially any convenient solvent. Preferablythe solvent comprises a ketone, and more preferably the ketone is methylethyl ketone, acetone, or methyl isobutyl ketone. More preferably stillthe ketone is methyl ethyl ketone. However, the conversion can ifdesired be performed in acetone. Alternatively, the conversion can beperformed in methyl isobutyl ketone.

Although the discussion and examples of this application illustrate thepreparation of tetrahydrobenzothiepine oxides having a para-substitutedphenyl group at the 5-position of the benzothiepine ring,tetrahydrobenzothiepine oxides having a meta-substituted phenyl group atthe 5-position can be prepared in a similar manner by selection of theproper starting materials. For example, use of a meta-substituted phenylanalog of a compound of Formula 7 in the applicable processes of thepresent application would yield the correspondingtetrahydrobenzothiepine oxide having a meta-substituted phenyl group atthe 5-position. The preparation of selected suitable starting materialsis disclosed in U.S. Pat. No. 5,994,391 (such as described in Examples1398a, 1400, 1425, 1426 and 1426a).

C. Detailed Preparative Methods

The starting materials for use in the methods of preparation of theinvention are known or can be prepared by conventional methods known toa skilled person or in an analogous manner to processes described in theart.

Generally, the process methods of the present invention can be performedas follows.

EXAMPLE 1 Preparation of1-chloro-2-(4-methoxyphenyl)methyl-4-nitrobenzene, 33

Step A. Preparation of 2-chloro-5-nitrophenyl-4′-methoxyphenyl ketone,34

Method 1

In an inert atmosphere, weigh out 68.3 g of phosphorus pentachloride(0.328 mole, Aldrich) into a 2-necked 500 mL round bottom flask. Fit theflask with a N₂ inlet adapter and suba seal. Remove from the inertatmosphere and begin N₂ purge. Add 50 mL of anhydrous chlorobenzene(Aldrich) to the PCl₅ via syringe and begin stirring with a magneticstir bar.

Weigh out 60 g of 2-chloro-5-nitrobenzoic acid (0.298 mole, Aldrich).Slowly add the 2-chloro-5-nitrobenzoic acid to the chlorobenzenesolution while under N₂ purge. Stir at room temperature overnight. Afterstirring at room temperature for about 20 hrs, place in an oil bath andheat at 50° C. for 1 hr. Remove chlorobenzene under high vacuum. Washthe residue with anhydrous hexane. Dry the acid chloride (wt=61.95 g).Store in inert and dry atmosphere.

In an inert atmosphere, dissolve the acid chloride in 105 mL ofanhydrous anisole (0.97 mole, Aldrich). Place solution in a 2-neck 500mL round bottom flask.

Weigh out 45.1 g of aluminum trichloride (0.34 moles, Aldrich) and placein a solid addition funnel. Fit the reaction flask with an additionfunnel and a N₂ inlet adapter. Remove from inert atmosphere. Chill thereaction solution with an ice bath an begin the N₂ purge. Slowly add theAlCl₃ to the chilled solution. After addition is complete, allow to warmto room temperature. Stir overnight.

Quench the reaction by pouring into a solution of 300 mL 1N HCl and ice.Stir for 15 min. Extract twice with ether. Combine the organic layersand extract twice with 2% NaOH, then twice with deionized H₂O. Dry overMgSO₄, filter, and rotovap to dryness. Remove the anisole under highvacuum. Crystallize the product from 90% ethanol/10% ethyl acetate. Dryon a vacuum line. Wt=35.2 g. yield 41%. Mass spec (m/z=292).

Method 2.

Change 230 kg of 2-chloro-5-nitrobenzoic acid (CNBA) to a clean dryreactor flushed with N₂. Seal the reactor and flush with N₂. To thereactor charge 460 kg of anisole. Start agitation and heat the mixtureto 90° C., dissolving most of the CNBA. To the reactor charge 785 kg ofpolyphosphoric acid (PPA). PPA containers are warmed in a hot box (70°C.) prior to charging in order to lower viscosity. Two phases result.The upper phase contains the majority of the CNBA and anisole. The lowerphase contains most of the PPA. The reaction conditions are maintainedfor hr at which time sampling begins to determine residual CNBA.Analysis of samples is by gas chromatography. The reaction is quenchedwhen 1.0% residual CNBA is achieved. The reaction is quenched into 796kg H₂O. The temperature of the quenched mass is adjusted to 60° C. andmaintained at this temperature until isolation. Agitation is stopped andthe phases are split. The lower spent acid phase is sent to wastedisposal. The upper product phase is washed with 18 kg of sodiumbicarbonate in 203 kg of water, then washed with 114 kg of potablewater. Agitation is stopped and the phases are split. The upper aqueousphase is sent to waste disposal. The lower product phase is cooled toabout 0° C. and 312 kg of heptane is added. A mixture of ortho- andpara-substituted product (total kg) precipitates out of solution and isrecovered by pressure filtration. To the product phase is added another134 kg of heptane causing another 317 kg of a mixture of ortho- andpara-substituted product to precipitate. The precipitate is recovered bypressure filtration. The wetcake is washed with heptane to removeresidual anisole. The wetcake is dried in a rotary vacuum dryer at 60°C. Final yield of 34 is 65.1% (30.3% yield of the ortho-substitutedproduct).

Step B. Preparation of1-chloro-2-(4-methoxyphenyl)methyl-4-nitrobenzene, 33

To a clean dry nitrogen purged 500 mL round bottom flask was charged60.0 g (0.206 moles) of 34. Trifluoroacetic acid (100 grams, ca. 67 mL)was added to the reactor and the resulting suspension was heated to 30°C. to give a homogeneous wine colored solution. Next, 71.0 g (0.611moles) of triethylsilane was placed in an addition funnel and 1.7 g(0.011 moles) of trifluoromethanesulfonic acid (triflic acid) was addedto reactor. The color changed from burgundy to greenish brown.Triethylsilane was added dropwise to the solution at 30° C. The batchcolor changed to a grass green and an exothermic reaction ensued. Theexotherm was allowed to raise the batch temperature to 45° C. withminimal cooling in a water bath. The reaction temperature was controlledbetween 45-50° C. for the duration of addition. Addition oftriethylsilane was complete in 1 hour. The batch color became greenishbrown at completion. The batch was stirred for three more hours at 40°C., then allowed to cool. When the batch temperature reached ca. 30° C.,product started to crystallize. The batch was further cooled to 1-2° C.in a water/ice bath, and after stirring for another half hour at 1-2°C., the slurry was filtered. The crystalline solid was washed with two60 mL portions of hexane, the first as a displacement wash and thesecond as a reslurry on the filter. The solids were vacuum filtereduntil dry on the filter under a stream of nitrogen and the solids werethen transferred to a clean container. A total of 49.9 grams of materialwas isolated. Mp 87.5-90.5° C. and HNMR identical with known samples of33. GC (HP-5 25 meter column, 1 mL N₂/min at 100° C., FID detection at300° C., split 50:1) of the product showed homogeneous material. Theisolated yield was 88% of 33.

EXAMPLE 2 Preparation of 2,2-dibutyl-1,3-propanediol, 54

(This method is similar to that described in U.S. Pat. No. 5,994,391,Example Corresponding to Scheme XI, Step 1, column 264.) Lithiumaluminum hydride (662 ml, 1.2 equivalents, 0.66 mol) in 662 mL of 1M THFwas added dropwise to a stirred solution of dibutyl-diethylmalonate (150g, 0.55 mol) (Aldrich) in dry THF (700ml) while maintaining thetemperature of the reaction mixture at between about −20? C. to about 0?C. using an acetone/dry ice bath. The reaction mixture was then stirredat room temperature overnight. The reaction was cooled to −20? C. and 40ml of water, 80 ml of 10% NaOH and 80 ml of water were successivelyadded dropwise. The resulting suspension was filtered. The filtrate wasdried over sodium sulfate and concentrated under vacuum to give 98.4 g(yield 95%) of the diol as an oil. Proton NMR, carbon NMR and MSconfirmed the product.

Alternate reducing agents that will be useful in this preparation ofcompound 54 include diisobutylaluminum hydride (DIBAL-H) or sodiumbis(2-methoxyethyxy)aluminum hydride (for example, Red-Al supplied byAldrich).

EXAMPLE 3 Preparation of 1-bromo-2-butyl-2-(hydroxymethyl)hexane, 52

A 250 mL 3-necked round-bottomed flask was fitted with a mechanicalstirrer, a nitrogen inlet, an addition funnel or condenser or distillinghead with receiver, a thermocouple connected to a J-Kem temperaturecontroller and a thermocouple connected to analog data acquisitionsoftware, and a heating mantle. The flask was purged with nitrogen andcharged with 20 grams of 54. To this was added 57 grams of a 30 wt. %solution of HBr in acetic acid. The mixture was heated to 80° C. for 4hrs. The solvents were distilled off to a pot temperature of 125° C.over 20 minutes. This removes most of the residual HBr. The mixture wascooled to 80° C. and 100 mL of Ethanol 2B (source: Aaper) was added atonce. Next 1.0 mL, of concentrated sulfuric acid was added. The solventwas distilled off (10 to ml solvent at 79-80° C.). And the mixture wasrefluxed for 2 h. An additional 10 to 15 ml of solvent was distilled offand the mixture was again held at reflux temperature for 2 h. Furthersolvent was distilled off to a pot temperature of 125° C. and then theflask contents were cooled to 25.0° C. To the flask was added 100 mL ofethyl acetate and 100 mL, of 2.5N sodium hydroxide. The mixture wasagitated for 15 minutes and the aqueous layer was separated. Another 100ml of water was added to the pot and the contents were agitated 15minutes. The aqueous layer was separated and solvent was distilled offto a pot temperature of 125° C. During this process water is removed byazeotropic distillation with ethyl acetate. The product was concentratedunder reduced pressure to afford 26.8 g of a brown oil containing theproduct 52 (96.81% by GC: HP1 column; initial temp. 50° C., hold for 2.5min, Ramp 10° C./min to ending temp. 275° C., final time 15 min).

EXAMPLE 3a Alternate Preparation of1-bromo-2-butyl-2-(hydroxymethyl)hexane, 52

A 250 mL 3-necked round-bottomed flask is fitted with a mechanicalstirrer, a nitrogen inlet, an addition funnel or condenser or distillinghead with receiver, a thermocouple connected to a J-Kem temperaturecontroller and a thermocouple connected to analog data acquisitionsoftware, and a heating mantle. The flask is purged with nitrogen andcharged with 20 grams of 54. To this is added 57 grams of a 30 wt. %solution of HBr in acetic acid. The mixture is heated to 80° C. for 4hrs. The solvents are vacuum distilled off to a pot temperature of 90°C. over 20 minutes. This removes most of the residual HBr. The mixtureis cooled to 80° C. and 100 mL of Ethanol 2B (source: Aaper) is added atonce. Next 1.0 mL of concentrated sulfuric acid is added. The solvent isdistilled off (10 to 15 ml solvent at 79-80° C.). And the mixture isrefluxed for 2h. An additional 10 to 15 ml of solvent is distilled offand the mixture is again held at reflux temperature for 2 h. Furthersolvent is distilled off to a pot temperature of 85° C. and then theflask contents are cooled to 25.0° C. To the flask is added 100 mL ofethyl acetate and 100 mL of 2.5N sodium hydroxide. The mixture isagitated for 15 minutes and the aqueous layer is separated. Another 100mL of water is added to the pot and the contents are agitated 15minutes. The aqueous layer is separated and solvent is distilled off toa pot temperature of 85° C. During this process water is removed byazeotropic distillation with ethyl acetate. The material is concentratedunder reduced pressure to afford the product 52.

EXAMPLE 4 Preparation of 2-(bromomethyl)-2-butylhexanal, 53

A 500 mL 3-necked round-bottom flask was fitted with a mechanicalstirrer, a nitrogen inlet, an addition funnel or condenser or distillinghead with receiver, a thermocouple connected to a J-Kem temperaturecontroller and a thermocouple connected to analog data acquisitionsoftware, and a heating mantle. The flask was purged with nitrogen gasand charged with 26.0 grams of 52 and 15.6 grams of triethylamine. In a250 ml flask was slurried 37.6 grams of sulfur trioxide-pyridine in 50mL of DMSO. The DMSO slurry was added to the round-bottom flask byaddition funnel over 15 min. The addition temperature started at 22° C.and reached a maximum of 41.0° C. (Addition of the slurry attemperatures below 18.0° C. will result in a very slow reaction,building up sulfur trioxide with will react rapidly when the temperaturerises above 25° C.) The mixture was stirred for 15 minutes. To themixture was added 100 mL of 2.5M HCl over minutes. The temperature wasmaintained below 35° C. Next, 100 mL of ethyl acetate was added and themixture was stirred 15 minutes. The mixture was then cooled to ambientand the aqueous layer was separated. To the pot was added 100 mL ofwater and the mixture was agitated for 15 minutes. The aqueous layer wasseparated. The solvent was distilled to a pot temperature of 115° C. andthe remaining material was concentrated under reduce pressure to afford21.8 g of a brown oil containing the product 53 (95.1% by GC: HP1column; initial temp. 50° C., hold for 2.5 min, Ramp 10° C./min toending temp. 275° C., final time 15 min).

EXAMPLE 4a Alternate Preparation and Purification of2-(Bromomethyl)-2-butylhexanal, 53

a. Preparation of Compound 52

To the reactor is charged 2,2-dibutyl-1,3-propanediol followed by 30 wt% HBr in acetic acid. The vessel is sealed and heated at an internaltemperature of ca. 80° C. and held for a period of ca. 7 hours, pressuremaintained below 25 psia. A GC of the reaction mixture is taken todetermine reaction completion (i.e., conversion of2,2-dibutyl-1,3-propanediol into 3-acetoxy-2,2-dibutyl-1-propanol). Ifthe reaction is not complete at this point, the mixture may be heatedfor an additional period of time to complete the conversion. Aceticacid/HBr is then removed using house vacuum (ca. 25 mmHg) up to amaximum internal temperature of ca. 90° C. Ethanol is then addedfollowed by sulfuric acid. A portion of the ethanol is removed (ca.one-quarter of the ethanol added) via atmospheric distillation. Ethanolis then added back (ca. the amount removed during the distillation) tothe reactor containing the 3-acetoxy-2,2-dibutyl-1-propanol and thecontents are heated to reflux (ca. 80° C. with a jacket temperature of95° C.) and then held at reflux for ca. 8 hours. Ethanol is then removedvia atmospheric distillation up to a maximum internal temperature of 85°C., using a jacket temperature of 95° C. A GC is taken to determinereaction completion (i.e., conversion of3-acetoxy-2,2-dibutyl-1-propanol to compound 52). If the reaction is notcomplete, ethanol is added back to the reactor and the contents areheated to reflux and then held at reflux for an additional 4 hours (ca.80° C., with a jacket of 95° C.). Ethanol is then removed viaatmospheric distillation up to a maximum internal temperature of 85° C.,using a jacket temperature of 95° C. A GC is taken to determine reactioncompletion (i.e., conversion of 3-acetoxy-2,2-dibutyl-1-propanol tocompound 52). Once the reaction is deemed to be complete, the remainingethanol is removed via atmospheric distillation up to a maximum internaltemperature of 125° C. Methyl t-butyl ether is then added followed by a5% sodium bicarbonate solution. The layers are separated, the aqueouslayer is extracted once with MTBE, the organic extracts are combined,washed once with water, dried over MgSO₄, and concentrated under housevacuum (ca. 25 mmHg) to a maximum internal temperature of 60° C. Theresultant oil is stored in the cooler until it is needed for furtherprocessing.

b. Preparation of Compound 53

Methyl sulfoxide is charged to the reactor followed by compound 52 andtriethylamine. Pyridine-sulfur trioxide complex is then addedportion-wise to the reactor while maintaining an internal temperature of<35° C. Once the pyridine-sulfur trioxide complex addition is complete,a GC of the reaction mixture is taken to determine reaction completion(i.e., conversion of 52 into 53). If the reaction is not complete atthis point, the mixture may be stirred for an additional period of timeto complete the conversion. The reaction is quenched with an 11 wt %aqueous HCl solution. Ethyl acetate is added and the layers areseparated, the aqueous layer is extracted once with ethyl acetate, theorganic extracts are combined, washed once with water, dried over MgSO₄,and concentrated under house vacuum (ca. 25 mm/Hg) to a maximum internaltemperature of 30° C. The resultant oil is stored in the cooler until itis needed for further processing.

c. Alternate Preparation of Compound 53

Compound 52 and methylene chloride are charged to the reactor followedby TEMPO. The solution is cooled to ca. 0-5° C. Potassium bromide andsodium bicarbonate are dissolved in a separate reactor and added to thesolution of 52 and TEMPO at 0-5° C. The biphasic mixture is cooled to0-5° C. and sodium hypochlorite is added at such a rate to maintain aninternal temperature of 0-5° C.

When the add is complete a GC of the reaction mixture is performed todetermine reaction completion. If the reaction is not complete (>1% 52remaining), additional sodium hypochlorite may be added to drive thereaction to completion. Immediately after the reaction is determined tobe complete, an aqueous solution of sodium sulfite is added to quenchthe remaining sodium hypochlorite. The layers are separated, the aqueouslayer is back-extracted with methylene chloride, the combined organicfractions are washed and dried over sodium sulfate. Compound 53 is thenconcentrated via a vacuum distillation, up to a maximum internaltemperature of ca. 30° C. The crude aldehyde is stored in the cooleruntil it is required for further processing.

d. Purification of Compound 53

A Wiped Film Evaporated (WFE) apparatus is set up with the followingconditions: evaporator temperature of 90° C., vacuum of ca. 0.2 mmHg anda wiper speed of 800 rpm's. The crude compound 53 is fed at a rate of1.0-1.5 kilograms of crude per hour. The approximate ratio of product toresidue during distillation is 90:10.

EXAMPLE 5 Preparation of1-(2,2-dibutyl-S,S-dioxido-3-oxopropylthio)-2-((4-methoxyphenyl)methyl)-4-nitrobenzene,30

A 1000 mL 4 neck jacketed Ace flask was fitted with a mechanicalstirrer, a nitrogen inlet, an addition funnel or condenser or distillinghead with receiver, a thermocouple, four internal baffles and a 28 mmTeflon turbine agitator. The flask was purged with nitrogen and chargedwith 75.0 grams of 33. Next, the flask was charged with 315.0 grams ofdimethylacetamide (DMAC), agitation was started and the mixture washeated to 30° C. Sodium sulfide (39.2 grams) was dissolved in 90 mlwater in a separate flask. The aqueous sodium sulfide solution wascharged into the flask over a 25 minute period. Temperature reached 37°C. at completion of addition. The solution turned dark red immediatelyand appeared to form a small amount of foam-like globules that adheredto the wall of the reactor. The temperature was held for two hrs at 40°C. To the flask was charged 77.9 grams of 53 all at once. The reactionmixture was heated to 65° C. and held for 2 hrs. Next 270 ml water wasadded at 65° C. The mixture was agitated 15 minutes. To the flask wasthen charge 315 ml of benzotrifluoride and the mixture was agitated 15minutes. The aqueous layer was separated at 50° C. The organic layer waswashed with 315 ml of 3% sodium chloride solution. The aqueous layer wasseparated at 50° C. The solvent was distilled to a pot temperature of63° C. at 195 to 200 mmHg. The flask contents were cooled to 60° C. andto it was charged 87.7 grams of trimethyl orthoformate, and 5.2 grams ofp-toluenesulfonic acid dissolved in 164.1 mL of methanol. The mixturewas heated to reflux, 60 to 65° C. for 2 hours. The solvent wasdistilled to a pot temperature of 63° C. at 195 to 200 mmHg to removemethanol and methylformate. The flask was then charged with 252 mlbenzotrifluoride and then cooled to 15° C. Next 22.2 grams sodiumacetate as a slurry in 30 ml water was added to the flask. The flask wasthen charged with 256.7 grams of commercial peracetic acid (nominally30-35% assay) over 20 minutes, starting at 15° C. and allowing theexotherm to reach 30 to 35° C. The addition was slow at first to controlinitial exotherm. After the first equivalent was charged the exothermsubsided. The mixture was heated to 30° C. and held for 3 hours. Theaqueous layer was separated at 30° C. The organic layer was washed with315 ml 6% sodium sulfite. The aqueous layer was separated. The flask wasthen charged with 40% by wt. sulfuric acid and heated to 75° C. for 2hrs. The aqueous layer was separated from the bottom at 40 to 50° C. Tothe flask was added 315 ml saturated sodium bicarbonate and the contentswere stirred for 15 minutes. The aqueous layer was separated. Thesolvent was distilled to a reactor temperature of 63° C. at 195 to 200mmHg. Next, 600 ml isopropyl alcohol was charged over 10 minutes and thetemperature was maintained at 50° C. The reactor was cooled to 38° C.and held for 1 hour. (The product may oil slightly at first thencrystallize during the hold period. If product oils out at 38° C. ordoes not crystallize it should be seeded to promote crystallizationbefore cooling.) The reactor was cooled to 15° C. over 30 minutes thenheld for 60 minutes. The solids were filtered and dried to yield 102.1grams of a crystalline yellow solid. Wash with 150 ml 10° C. IPA.Analysis by BPLC (Zorbax RX-C8 column, 0.1% aq. TFA/acetonitrilegradient mobile phase, UV detection at 225 nm) showed 97.7% by weight of30, 79.4% isolated molar corrected yield.

EXAMPLE 5a Alternate Preparation of1-(2,2-dibutyl-S,S-dioxido-3-oxopropylthio)-2-((4-methoxyphenyl)methyl)-4-nitrobenzene,30

Step 1. Preparation of Sulfide Aldehyde Compound 69

A 1000 mL 4 neck jacketed Ace reator is fitted with a mechanicalstirrer, nitrogen inlet, additional funnel, a thermocouple, fourinternal baffles, and a 28 mm Teflon turbine agitator. The flask ispurged with nitrogen gas and charged with 145 g of compound 33 and 609mL of N,N-dimethylacetamide (DMAC). Agitation is started and the mixtureis heated to 30° C. In a separate flask 72.3 g of Na₂S (Spectrum) isdissolved in 166.3 mL of water. The aqueous Na₂S is charged to the flaskover a period of about 90 minutes. Addition rate should be adjusted tomaintain the reaction temperature below 35° C. The mixture is stirred at35° C. for 2 hours and then 150.7 g of compound 53 is added all at once.The mixture is heated to 70° C. and held for 2 hours. To the mixture isadjusted to 50° C., to it is added 442.7 mL water and the mixture isagitated for 15 minutes. To the reactor is then charged 609 mL ofbenzotrifluoride followed by 15 minutes of agitation. The aqueous layeris separated at 50° C. The organic layer is washed with 3% aq. NaCl. Theaqueous layer is separated at 50° C. The organic layer contains compound69. The organic layer is stable and can be held indefinitely.

Step 2. Preparation of Compound 70

The solvent is distilled at about 63° C. to 66° C. and 195 to 200 mmHgfrom the organic layer resulting from Step 1 until a third to a half ofthe benzotrifluoride volume is distilled. The mixture is cooled to about60° C. and charged with 169.6 g of trimethylorthoformate and about 10 gof p-toluenesulfonic acid dissolved in 317.2 mL of methanol. (Note:alternate orthoformates, for example triethylorthoformate, can be usedin place of trimethylorthoformate to obtain other acetals.) The reactoris fitted with a condenser and a distillation head. The mixture isheated to boiling and from it is distilled 5 mL of methanol to removeresidual water from the condenser and the mixture is held at reflux at60° C. to 65° C. for about 2 hours. Solvent is then distilled to a pottemperature of 60° C. to 66° C. at 195 to 200 mm Hg to remove methanoland methylformate. To the mixture is added 355.4 mL benzotrifluoride andthe mixture is cooled to 15° C. To the reactor is charged 32.1 g sodiumacetate slurried in 77.2 mL water. The reaction is held for 72 hours. Tothe reactor is then charged 340.4 g of peracetic acid over a 2 hourperiod starting at 15° C. Addition was adjusted to keep the temperatureat or below 20° C. The mixture was then heated to 25° C. for 4 hours.The aqueous (top) layer was separated at 25° C. and the organic layerwas washed with 190 mL of 10% sodium sulfite. The organic layer containscompound 70 and can be stored indefinitely.

Step 3. Preparation of Compound 30

To the organic layer of Step 2 is added 383.8 g of concentrated sulfuricacid. The mixture is heated at 75° C. for 2 hours and the aqueous(bottom) layer is separated at 40 to 50° C. To the reactor is charged609 mL of 10% sodium bicarbonate and the mixture is stirred for 15minutes. The aqueous (top) layer is separated. Solvent is distilled fromthe organic layer at 63 to 66° C. at 195 to 200 mm Hg. To the reactor ischarged 1160 mL of isopropyl alcohol over 10 minutes at 50° C. Thereactor is cooled to 38° C. and held for 1 hour. Some crystallizationoccurs. The reactor is cooled to 15° C. over 30 minutes and held for 120minutes, causing further crystallization of 30. The crystals arefiltered and dried to yield 200.0 g of a crystalline yellow solid. Thecrystals of 30 are washed with 290 mL of 10° C. isopropyl alcohol.

EXAMPLE 6 Preparation of1-(2,2-dibutyl-S,S-dioxido-3-oxopropylthio)-2-((4-methoxyphenyl)methyl)-4-dimethylaminobenzene,29

A 300 ml autoclave was fitted with a Stirmix hollow shaft gas mixingagitator, an automatic cooling and heating temperature control, and anin-reactor sampling line with sintered metal filter. At 20° C. theautoclave was charged with 15.0 grams of 30, 2.5 grams of Pd/C catalyst,60 grams of ethanol, 10.0 grams of formaldehyde (36% aqueous solution),and 0.55 grams of concentrated sulfuric acid. The reactor was closed andpressurized the reactor to 60 psig (515 kPa) with nitrogen to check forleakage. The pressure was then reduced to 1-2 psig (108-115 kPa). Thepurge was repeated three times. The autoclave was then pressurized withH₂ to 60 psig (515 kPa) while the reactor temperature was held at 22° C.The agitator was started and set to 800-1000 rpm and the reactortemperature control is set at 30-40° C. When the cooling capacity wasnot enough to control the temperature, the agitator rpm or the reactorpressure was reduced to maintain the set temperature. After about 45minutes when the heat release was slowing down (about 70% of hydrogenusage was reacted), the temperature was raised to 60° C. Hydrogen wasthen released and the autoclave was purged with nitrogen three times.The content of the reactor was pressure filtered through a sinteredmetal filter at 60° C. The filtrate was stirred to cool to the roomtemperature over 1-2 hours and 50 grams of water was added over 1 hour.The mixture was stirred slowly at 4° C. overnight and filtered through aBuche type filter. The cake was air dried to give 13.0 grams of 29 with99+% assay. The isolated yield was 89%.

EXAMPLE 7 Preparation ofsyn-3,3-dibutyl-7-(dimethylamino)-1,1-dioxido-4-hydroxy-5-(4-methoxyphenyl)-2,3,4,5-tetrahydrobenzothiepine,syn-24

A 250 ml round bottom glass reactor fitted with mechanical agitator anda heating/cooling bath was purged with nitrogen. Forty-five grams ofpotassium t-butoxide/THF solution were charged to the reactor andagitation was started. In a separate container 18 grams of 29 wasdissolved in 25 grams of THF. The 29/THF solution was charged into thereactor through a addition funnel over about 2.0 hours. The reactortemperature was controlled between about 16-20° C. Salt precipitatedafter about half of 29 was added. The slurry was stirred at 16-20° C.for an hour. The reaction was quenched with 54 grams of 7.4% ammoniumchloride aqueous solution over a period of about 30 minutes whilekeeping the reactor temperature at 16-24° C. The mixture was gentlystirred until all salt is dissolved (about 10 minutes). Agitation wasstopped and the phases were allowed to separate. The aqueous layer wasdrained. The organic layer was charged with 50 ml water and 25 grams ofisopropyl alcohol. The agitator was started and crystallization wasallowed to take place. The THF was distilled under the ambient pressure,with b.p. from 60 to 65° C. and pot temperature from 70 to 77° C. Thecrystals dissolved as the pot gets heated and reappeared when the THFstarted to distill. After distillation was complete, the slurry wasslowly cooled to 4° C. over 2-3 hours and stirred slowly for severalhours. The slurry was filtered with a 150 ml Buche filter and the cakewas washed with 10 grams of cold 2:1 water/isopropyl alcohol solution.Filtration was complete in about minutes. The cake was air dried to give16.7 grams of syn-24 with 99+% assay and a 50/50 mixture of R,R and S,Sisomers.

EXAMPLE 8a Conditions for Optical Resolution of Compound (4R,5R)-24

The following simulated moving bed chromatography (SMB) conditions areused to separate the (4R,5R) and (4S,5S) enantiomers of compound syn-24.

Column (CSP): Daicel Chiralpak AS Mobile Phase: acetonitrile (100%)Column Length:  11 cm (9 cm for column 6) Column I.D.:  20.2 cm Numberof Columns:  6 columns Feed Concentration:  39 grams/liter EluentFlowrate: 182 L/hour Feed Flowrate:  55 L/hour Extract Flowrate: 129.4L/hour Raffinate Flowrate: 107.8 L/hour Recycling Flowrate: 480.3 L/hourPeriod:  0.6 minute Temperature: ambient

SMB performance:

Less retained enantiomer purity (%): 92.8%

Less retained enantiomer concentration: 10 g/L

More retained enantiomer recovery yield (%): 99.3%

More retained enantiomer concentration: 7 g/L

EXAMPLE 8b Alternate Conditions for Optical Resolution of Compound(4R,5R)-24

The following simulated moving bed chromatography (SMB) conditions areused to separate the (4R,5R) and (4S,5S) enantiomers of compound syn-24.

Column (CSP): di-methyl phenyl derivative of tartaric acid (KromasilDMB) Mobile Phase: toluene/methyl tert-butyl ether (70/30) ColumnLength: 6.5 cm Column I.D.: 2.12 cm Number of Columns: 8 columns Zones:2-3-2-1 Feed Concentration: 6.4 weight percent Eluent Flowrate: 20.3g/minute Feed Flowrate: 0.7 g/minute Extract Flowrate: 5.0 g/minuteRaffinate Flowrate: 16.0 g/minute Period: 8 minute Temperature: ambient

SMB performance:

Less retained enantiomer purity (%): >98%

Less retained enantiomer recovery yield (%): >95%

EXAMPLE 8c Alternate Conditions for Optical Resolution of Compound(4R,5R)-24

The following simulated moving bed chromatography (SMB) conditions areused to separate the (4R,5R) and (4S,5S) enantiomers of compound syn-24.

Column (CSP): di-methyl phenyl derivative of tartaric acid (KromasilDMB) Mobile Phase: toluene (100%) Column Length: 6.5 cm Column I.D.:2.12 cm Number of Columns. 8 columns Zones: 2-3-2-1 Feed Concentration:64 weight percent Eluent Flowrate: 20.3 g/minute Feed Flowrate: 0.5g/minute Extract Flowrate: 4.9 g/minute Raffinate Flowrate: 15.9g/minute Period: 8 minute Temperature: ambient

SMB performance:

Less retained enantiomer purity (%): >98%

Less retained enantiomer recovery yield (%): >95%

EXAMPLE 8d Racemization of Compound (4S,5S)-24

A 250 mL round bottom glass reactor with mechanical agitator and aheating/cooling bath is purged with nitrogen gas. In a flask, 18 g of(4S,5S)-24 (obtained as the more retained enantiomer in Examples 8a-8c)is dissolved in 50 g of dry TBF. This solution is charged into thereactor and brought to about 23-25° C. with agitation. To the reactor ischarged 45 g of potassium t-butoxide/THF solution (1 M, Aldrich) throughan addition funnel over about 0.5 hour. A slurry forms. Stir the slurryat about 24-26° C. for about 1-1.5 hours. The reaction is quenched with54 g of 7.5% aqueous ammonium chloride while keeping the reactortemperature at about 23-26° C. The first ca. 20% of the ammoniumchloride solution is charged slowly until the slurry turns thin and therest of the ammonium chloride solution is charged over about 0.5 hour.The mixture is stirred gently until all the salt is dissolved. Theagitation is stopped and the phases are allowed to separate. The aqueouslayer is removed. To the organic layer is charged 50 mL of water and 25g of isopropyl alcohol. The agitator is started and crystallization isallowed to take place. THF is removed by distillation at ambientpressure. The crystals dissolve as the pot warms and then reappear whenthe THF starts to distill. The resulting slurry is cooled slowly to 4°C. within 2-3 hours and slowly stirred for 1-2 hours. The slurry isfiltered with a 150 mL Buche filter and washed with 20 g of 0-4° C.isopropyl alcohol. The cake is air dried at about 50-60° C. under vacuumto give 16.7 g of racemic 24.

EXAMPLE 9 Preparation of(4R,5R)-3,3-dibutyl-7-(dimethylamino)-1,1-dioxido-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine,(4R,5R)-28

A 1000 mL 4 neck Reliance jacketed reactor flask was fitted with amechanical stirrer, a nitrogen inlet, an addition funnel, condenser ordistillation head with receiver, a thermocouple, and a Teflon paddleagitator. The flask was purged with nitrogen gas and was charged with41.3 grams of (4R,5R)-24 and 18.7 grams of methionine followed by 240grams of methanesulfonic acid. The mixture was heated to 75° C. andstirred for 8 hrs. The mixture was then cooled to 25° C. and chargedwith 480 mL of 3-pentanone. The solution was homogeneous. Next, theflask was charged with 320 mL of dilution water and was stirred for 15minutes. The aqueous layer was separated and to the organic layer wasadded 250 mL of saturated sodium bicarbonate. The mixture was stirredfor 15 minutes and the aqueous layer was separated. Solvent wasdistilled to approximately one-half volume under vacuum at 50° C. Theflask was charged with 480 mL of toluene, forming a clear solution.Approximately half the volume of solvent was removed at 100 mmHg. Themixture was cooled to 10° C. and stirred overnight. Crystals werefiltered and washed with 150 mL cold toluene and allowed to dry undervacuum. Yielded 29.9 g with a 96.4 wt % assay. The filtrate wasconcentrated and toluene was added to give a second crop of 2.5 grams ofcrystals. A total of 32.1 g of dry off white crystalline (4R,5R)-28 wasobtained.

EXAMPLE 9a Alternate Preparation of(4R,5R)-3,3-dibutyl-7-(dimethylamino)-1,1-dioxido-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine,(4R,5R)-28

A 1000 mL 4 neck Ace jacketed reactor flask is fitted with a mechanicalstirrer, a nitrogen inlet, an addition funnel, condenser or distillationhead with receiver, a thermocouple, and a Teflon paddle agitator. Theflask is purged with nitrogen gas and is charged with 40.0 grams of(4R,5R)-24 and 17.8 grams of methionine followed by 178.6 grams ofmethanesulfonic acid. The mixture is heated to 80° C. and stirred for 12hrs. The mixture is then cooled to 15° C. and charged with 241.1 mL ofwater over 30 minutes. The reactor is then charged with 361.7 mL of3-pentanone. Next, the flask is stirred for 15 minutes. The aqueouslayer is separated and to the organic layer is added 361.7 mL ofsaturated sodium bicarbonate. The mixture is stirred for 15 minutes andthe aqueous layer was separated. Solvent is distilled to approximatelyone-half volume under vacuum at 50° C. Crystals start to form at thistime. The flask is charged with 361.7 mL of toluene and the mixture iscooled to 0° C. Crystals are allowed to form. Crystals are filtered andwashed with 150 mL cold toluene and allowed to dry under vacuum at 50°C. Yield 34.1 g of off-white crystalline (4R,5R)-28.

EXAMPLE 9b Alternate Preparation of(4R,5R)-3,3-dibutyl-7-(dimethylamino)-1,1-dioxido-4-hydroxy-5-(4-hydroxyphenyl)-2,3,4,5-tetrahydrobenzothiepine,(4R,5R)-28

A first 45 L reactor is purged with nitrogen gas. To it is charged 2.5kg of (4R,5R)-24 followed by 1.1 kg of methionine and 11.1 kg ofmethanesulfonic acid. The reaction mixture is heated to 85° C. withagitation for 7 hours. The reaction mixture is then cooled to 5° C. and17.5 L of water is slowly charged to the first reactor. The reactiontemperature will reach about 57° C. Next, 17.5 L of methyl isobutylketone (MIBK) are charged to the first reactor and the reaction mixtureis stirred for 30 minutes. The mixture is allowed to stand for 30minutes and the layers are separated. The aqueous phase is transferredto a second 45 L reactor and 10 L of MIBK is charged to the secondreactor. The second reactor and its contents are stirred for 30 minutesand then allowed to stand for 30 minutes while the layers separate. Theorganic phase is separated from the second reactor and the two organicphases are combined in the first reactor. To the first reactor iscarefully charged 1.4 kg of aqueous sodium bicarbonate. The mixture isstirred for 30 minutes and then allowed to stand for 30 minutes. Thephases are separated. If the pH of the aqueous phase is less than 6 thena second bicarbonate wash is performed. After the bicarbonate wash, 15 Lof water is charged to the first reactor and the mixture is heated to40° C. The mixture is stirred for 30 minutes and then allowed to standfor 30 minutes. The phases are separated. The organic phase isconcentrated by vacuum distillation so that approximately 5 L of MIBKremain in the concentrate. The distillation starts when the batchtemperature is at 35° C. at 1 psia. The distillation is complete whenthe batch temperature reaches about 47.8° C. The batch temperature isthen adjusted to 45° C. and 20 L of heptane is charged to the productmixture over 20 minutes. The resulting slurry is cooled to 20° C. Theproduct slurry is filtered (10 micron cloth filter) and washed with 8 Lof 20% MIBK/heptane solution. The product is dried on the filter at 80°C. for 21 hours under vacuum. A total of 2.16 kg of white crystalline(4R,5R)-28 is isolated.

EXAMPLE 9c Batch Isolation of Compound (4R,5R)-28 (or Compound(4S,5S)-28) from Acetonitrile Solution

A 1 L reactor is equipped with baffles and a 4-blade radial flowturbine. The reactor is purged with 1 L of nigrogen gas and charged with300 mL of water. The water is stirred at a minimum rate of 300 rpm at 5°C. The reactor is charged with 125-185 mL of (4R,5R)-28 in acetonitrilesolution (20% w/w) at a rate of 1.4 mL/min. Upon addition, crystalsstart to form. After addition of the acetonitrile solution, crystals arefiltered through a Buchner funnel. The cake is washed with 3 volumes ofwater and/or followed by 1-2 volumes of ice cold isopropyl alcoholbefore drying. Alternatively, this procedure can be used on anacetonitrile solution of (4S,5S)-28 to isolate (4S,5S)-28.

EXAMPLE 9d Continuous Isolation of Compound (4R,5R)-28 (or Compound(4S,5S)-28) from Acetonitrile Solution

A 1 L reactor is equipped with baffles and a 4-blade radial flowturbine. The reactor is purged with 1 L of nigrogen gas and charged with60 grams of water and 30 grams of acetonitrile. The mixture is stirredat 300 rpm and 5° C. Into the reactor are fed 300 mL of water and 125 mLof 20% (w/w) (4R,5R)-28 in acetonitrile solution at rates of 1.7 mL/minand 1 mL/min, respectively. When the contents of the reactor reach70-80% of the volume of the reactor, the slurry can be drained to afilter down to a minimum stirring level in the reactor and followed bymore feeding. Alternatively, the reactor can be drained continuously asthe feeds continue. The water/acetonitrile ratio can be in the range ofabout 2:1 to about 3:1. Filtered cake can be handled as described inExample 9c. Alternatively, this procedure can be used on an acetonitrilesolution of (4S,5S)-28 to isolate (4S,5S)-28.

EXAMPLE 10 Preparation of 1-(chloromethyl)-4-(hydroxymethyl)benzene, 55

A reaction flask fitted with a nitrogen inlet and outlet, a refluxcondenser, and a magnetic stirrer was purged with nitrogen. The flaskwas charged with 25 g of 4-(chloromethyl)benzoic acid. The flask wascharged with 75 mL of THF at ambient temperature. Stirring caused asuspension to form. An endothermic reaction ensued in which thetemperature of the reaction mixture dropped 22° C. to 14° C. To thereaction mixture 175 mL of borane-THF adduct was added via a droppingfunnel over about 30 minutes. During this exothermic addition, anice-bath was used for external cooling to keep the temperature below 30°C. The reaction mixture was stirred at 20° C. for 1 h and it was thencooled to 0° C. The reaction mixture was quenched by slow addition of 1Msulfuric acid. The resulting reaction mixture was diluted with 150 mL oft-butyl methyl ether (TBME) and stirred for at least 20 min to destroyboric acid esters. The layers were separated and the aqueous layer waswashed with another portion of 50 mL of TBME. The combined organiclayers were washed twice with 100 mL of saturated sodium bicarbonatesolution. The organic layer was dried over 11 g of anhydrous sodiumsulfate and filtered. The solvents were evaporated on a rotaryevaporator at 45° C. (bath temperature) and <350 mbar yielding acolorless oil. The oil was seeded with crystals and the resulting solid55 was dried under vacuum. Yield: 19.7g (86%). Assay by GC (HP-5 25meter column, 1 mL N₂/min at 100° C., FID detection at 300° C., split50:1).

EXAMPLE 11 Preparation of(4R,5R)-1-((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-1-azoniabicyclo[2.2.2]octanechloride,

Step 1. Preparation of (4R,5R)-26

A 1000 mL 4 neck jacketed Ace reactor flask was fitted with a mechanicalstirrer, a nitrogen inlet, an addition funnel or condenser or distillinghead with receiver, a thermocouple, four internal baffles and a 28 mmTeflon turbine agitator. The flask was purged with nitrogen gas andcharged with 25.0 grams of (4R,5R)-28 and 125 mL ofN,N-dimethylacetamide (DMAC). To this was added 4.2 grams of 50% sodiumhydroxide. The mixture was heated to 50° C. and stirred for 15 minutes.To the flask was added 8.3 grams of 55 dissolved in 10 mL of DMAC, allat once. The temperature was held at 50° C. for 24 hrs. To the flask wasadded 250 mL of toluene followed by 125 mL of dilution water. Themixture was stirred for 15 minutes and the layers were then allowed toseparate at 50° C. The flask was then charged with 125 mL of saturatedsodium chloride solution and stirred 15 minutes. Layers separatedcleanly in 30 seconds at 50° C. Approximately half of the solvent wasdistilled off under vacuum at 50° C. The residual reaction mixturecontained (4R,5R)-26.

Step 2. Preparation of (4R,5R)-27

Toluene was charged back to the reaction mixture of Step 1 and themixture was cooled to 35° C. To the mixture was then added 7.0 grams ofthionyl chloride over minutes. The reaction was exothermic and reached39° C. The reaction turned cloudy on first addition of thionyl chloride,partially cleared then finally remained cloudy. The mixture was stirredfor 0.5 hr and was then washed with 0.25N NaOH. The mixture appeared toform a small amount of solids that diminished on stirring, and thelayers cleanly separated. The solvent was distilled to a minimum stirvolume under vacuum at 50° C. The residual reaction mixture contained(4R,5R)-27.

Step 3. Preparation of 41

To the reaction mixture of Step 2 was charged with 350 mL of methylethyl ketone (MEK) followed by 10.5 mL water and 6.4 grams ofdiazabicyclo[2.2.2]octane (DABCO) dissolved in 10 mL of MEK. The mixturewas heated to reflux, and BPLC showed <0.5% of (4R,5R)-27. The reactionremained homogenous initially then crystallized at the completion of thereaction. An additional 5.3 mL of water was charged to the flask toredissolve product. Approximately 160 mL of solvent was then distilledoff at atmospheric pressure. The mixture started to form crystals after70 mL of solvent was distilled. Water separated out of distillateindicating a ternary azeotrope between toluene, water and methyl ethylketone (MEK). The mixture was then cooled to 25° C. The solids werefiltered and washed with 150 mL MEK, and let dry under vacuum at 60° C.Isolated 29.8.0 g of off-white crystalline 41.

EXAMPLE 11a Alternate Preparation of(4R,5R)-1-((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-1-azoniabicyclo[2.2.2]octanechloride, Form II of 41

A 1000 mL 4 neck jacketed Ace reactor flask is fitted with a mechanicalstirrer, a nitrogen inlet, an addition funnel or condenser or distillinghead with receiver, a thermocouple, four internal baffles and a 28 mmTeflon turbine agitator. The flask is purged with nitrogen gas andcharged with 25.0 grams of (4R,5R)-28 and 100 mL ofN,N-dimethylacetamide (DMAC). The mixture is heated to 50° C. and to itis added 4.02 grams of 50% sodium hydroxide. The mixture is stirred forminutes. To the flask is added 8.7 grams of 55 dissolved in 12.5 mL ofDMAC, all at once. The charge vessel is washed with 12.5 mL DMAC and thewash is added to the reactor. The reactor is stirred for 3 hours. To thereactor is added 0.19 mL of 49.4% aq. NaOH and the mixture is stirredfor 2 hours. To the mixture is added 0.9 g DABCO dissolved in 12.5 mLDMAC. The mixture is stirred 30 to 60 minutes at 50° C. To the flask isadded 225 mL of toluene followed by 125 mL of dilution water. Themixture is stirred for 15 minutes and the layers are then allowed toseparate at 50° C. The bottom aqueous layer is removed but any rag layeris retained. The flask is then charged with 175 mL of 5% hydrochloricacid solution and stirred 15 minutes. Layers are separated at 50° C. toremove the bottom aqueous layer, discarding any rag layer with theaqueous layer. Approximately half of the solvent is distilled off undervacuum at a maximum pot temperature of 80° C. The residual reactionmixture contains (4R,5R)-26.

Step 2. Preparation of (4R,5R)-27

Toluene (225 mL) is charged back to the reaction mixture of Step 1 andthe mixture is cooled to 30° C. To the mixture is then added 6.7 gramsof thionyl chloride over 30 to 45 minutes. The temperature is maintainedbelow 35° C. The reaction turns cloudy on first addition of thionylchloride, then at about 30 minutes the layers go back together and forma clear mixture. The mixture is stirred for 0.5 hr and is then chargedwith 156.6 mL of 4% NaOH wash over a 30 minute period. The addition ofthe wash is stopped when the pH of the mixture reaches 8.0 to 10.0. Thebottom aqueous layer is removed at 30° C. and any rag layer is retainedwith the organic layer. To the mixture is charged 175 mL of saturatedNaCl wash with agitation. The layers are separated at 30° C. and thebottom aqueous layer is removed, discarding any rag layer with theaqueous layer. The solvent is distilled to a minimum stir volume undervacuum at 80° C. The residual reaction mixture contains (4R,5R)-27.

Step 3. Preparation of 41

To the reaction mixture of Step 2 is charged 325 mL of methyl ethylketone (MEK) and 13 mL water. Next, the reactor is charged 6.2 grams ofdiazabicyclo[2.2.2]octane (DABCO) dissolved in 25 mL of MEK. The mixtureis heated to reflux and held for 30 minutes. Approximately 10% ofsolvent volume is then distilled off. The mixture starts to formcrystals during distillation. The mixture is then cooled to 20° C. for 1hour. The off-white crystalline 41 (Form II) is filtered and washed with50 mL MEK, and let dry under vacuum at 100° C.

EXAMPLE 11b Alternate Preparation of(4R,5R)-1-((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-1-azoniabicyclo[2.2.2]octanechloride, Form II of 41

A 1000 mL 4 neck jacketed Ace reactor flask is fitted with a mechanicalstirrer, a nitrogen inlet, an addition funnel or condenser or distillinghead with receiver, a thermocouple, four internal baffles and a Teflonturbine agitator. The flask is purged with nitrogen gas and charged with25.0 grams of (4R,5R)-28 and 125 mL of N,N-dimethylacetamide (DMAC). Themixture is heated to 50° C. and to it is added 7.11 grams of 30% sodiumhydroxide over a period of 15 to 30 minutes with agitation. The mixtureis stirred for 30 minutes. To the flask is added 9.5 grams of solid 55.The reactor is stirred for 3 hours. To the mixture is added 1.2 g ofsolid DABCO. The mixture is stirred 30 to 60 minutes at 50° C. To theflask is added 225 mL of toluene followed by 125 mL of water. Themixture is stirred for 5 minutes and the layers are then allowed toseparate at 50° C. The bottom aqueous layer is removed but any rag layeris retained with the organic layer. The flask is then charged with 175mL of 5% hydrochloric acid solution and stirred 15 minutes. Layers areseparated at 50° C. to remove the bottom aqueous layer, discarding anyrag layer with the aqueous layer. The flask is then charged with 225 mLof water and stirred 15 minutes. The layers are allowed to separate at50° C. The bottom aqueous layer is removed, discarding any rag layerwith the aqueous layer. Approximately half of the solvent is distilledoff under vacuum at a maximum pot temperature of 80° C. The residualreaction mixture contains (4R,5R)-26.

Step 2. Preparation of (4R,5R)-27

Toluene (112.5 mL) is charged back to the reaction mixture of Step 1 andthe mixture is cooled to 25° C. To the mixture is then added 7.3 gramsof thionyl chloride over 15 to 45 minutes. The temperature of themixture is maintained above 20° C. and below 40° C. The reaction turnscloudy on first addition of thionyl chloride, then at about 30 minutesthe layers go back together and form a clear mixture. The mixture isthen charged with 179.5 mL of 4% NaOH wash over a 30 minute period. Themixture is maintained above 20° C. and below 40° C. during this time.The addition of the wash is stopped when the pH of the mixture reaches8.0 to 10.0. The mixture is then allowed to separate at 40° C. for atleast one hour. The bottom aqueous layer is removed and any rag layer isretained with the organic layer. To the mixture is charged 200 mL ofdilution water. The mixture is stirred for 15 minutes and then allowedto separate at 40° C. for at least one hour. The bottom aqueous layer isremoved, discarding any rag layer with the aqueous layer. The solvent isdistilled to a minimum stir volume under vacuum at 80° C. The residualreaction mixture contains (4R,5R)-27.

Step 3. Preparation of 41

To the reaction mixture of Step 2 is charged 350 mL of methyl ethylketone (MEK) and 7 mL water. The mixture is stirred for 15 minutes andthe temperature of the mixture is adjusted to 25° C. Next, the reactoris charged with 6.7 grams of solid diazabicyclo[2.2.2]octane (DABCO).The mixture is maintained at 25° C. for three to four hours. It is thenheated to 65° C. and maintained at that temperature for 30 minutes. Themixture is then cooled to 25° C. for 1 hour. The off-white crystalline41 (Form II) is filtered and washed with 50 mL MEK, and let dry undervacuum at 100° C.

EXAMPLE 12 Alternate Preparation of(4R,5R)-1-((4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzithiepin-5-yl)phenoxy)methyl)phenyl)methyl-4-aza-1-azoniabicyclo[2.2.2]octanechloride, Form I of 41

(4R,5R)-27 (2.82 kg dry basis, 4.7 mol) was dissolved in MTBE (9.4 L).The solution of (4R,5R)-27 was passed through a 0.2 mm filter cartridgeinto the feeding vessel. The flask and was rinsed with MTBE (2×2.5 L).The obtained solution as passed through the cartridge filter and addedto the solution of (4R,5R)-27 in the feeding vessel. DABCO(diazabicyclo[2.2.2]octane, 0.784 kg, 7.0 mol) was dissolved in MeOH(14.2 L). The DABCO solution was passed through the filter cartridgeinto the 100 L nitrogen-flushed reactor. The Pyrex bottle and thecartridge filter were rinsed with MeOH (7.5 L) and the solution wasadded to the reactor. The (4R,5R)-27 solution was added from the feedingvessel into the reactor at 37° C. over a period of 10 min, whilestirring. Methanol (6.5 L) was added to the Pyrex bottle and via thecartridge filter added to the feeding vessel to rinse the remaining(4R,5R)-27 into the reactor. The reaction mixture was brought to 50-60°C. over 10-20 min and stirred at that temperature for about 1 h. Themixture was cooled to 20-25° C. over a period of 1 h. To the reactionmixture, methyl t-butyl ether (MTBE) (42 L) was added over a period of 1h and stirred for a minimum of 1 h at 20-25° C. The suspension wasfiltered through a Büchner funnel. The reactor and the filter cake werewashed with MTBE (2×14 L). The solids were dried on a rotary evaporatorin a 20 L flask at 400−12 mbar, 40° C., for 22 h. A white crystallinesolid was obtained. The yield of 41 (Form I) was 3.08 kg (2.97 kg dry,93.8%) and the purity 99.7 area % (HPLC; Kromasil C 4, 250×4.6 mmcolumn; 0.05% TFA in H₂O/0.05% TFA in ACN gradient, UV detection at 215nm).

EXAMPLE 12a Conversion of Form I of Compound 41 into Form II of Compound41

To 10.0 grams of Form I of 41 in a 400 mL jacketed reactor is added 140mL of MEK. The reactor is stirred (358 rpm) for 10 minutes at 23° C. for10 minutes and the stirring rate is then changed to 178 rpm. Thesuspension is heated to reflux over 1 hour using a programmedtemperature ramp (0.95° C./minute) using batch temperature control(cascade mode). The delta T_(max) is set to 5° C. The mixture is held atreflux for 1 hour. The mixture is cooled to 25° C. After 3 hours at 25°C., a sample of the mixture is collected by filtration. Filtration israpid (seconds) and the filtrate is clear and colorless. The white solidis dried in a vacuum oven (80° C., 25 in. Hg) to give a white solid. Theremainder of the suspension is stirred at 25° C. for 18 hours. Themixture is filtered and the cake starts to shrink as the mother liquorreaches the top of the cake. The filtration is stopped and the reactoris rinsed with 14 mL of MEK. The reactor stirrer speed is increased from100 to 300 rpm to rinse the reactor. The rinse is added to the filterand the solid is dried with a rapid air flow for 5 minutes. The solid isdried in a vacuum oven at 25 in. Hg for 84 hours to give Form II of 41.

EXAMPLE 13 Preparation of 2-(phenylthiomethyl)hexanal

To a stirred mixture of n-butylacrolein (9.5 ml, 71.3 mmol) and Et₃N(0.5 mL, 3.6 mmol) at 0° C. under nitrogen is added thiophenol (7.3 mL,71.3 mmol) in 5 minutes. The mixture is allowed to warm to roomtemperature in 30 minutes. ¹H NMR of the reaction mixture sample willshow quantitative conversion. Et₃N is removed under reduced pressure.

EXAMPLE 14 Preparation of 2-((4-methoxyphenylthio)methyl)hexanal

To a stirred mixture of n-butylacrolein (2.66 ml, 20 mmol) and Et₃N(0.14 mL, 1 mmol) at 0° C. under nitrogen is added 4-methoxythiophenol(2.46 mL, 20 mmol) in 5 minutes. The mixture is allowed to warm to roomtemperature in 30 minutes. ¹HNMR of the reaction mixture sample willshow quantitative conversion. Et₃N is then removed under reducedpressure.

EXAMPLE 15 Preparation of 2-((4-chlorophenylthio)methyl)hexanal

To a stirred mixture of n-butylacrolein (5.32 ml, 40 mmol) and Et₃N(0.28 mL, 2 mmol) at 0° C. under nitrogen is added 4-chlorothiophenol(5.78 g, 40 mmol) in 5 minutes. The mixture is allowed to warm to roomtemperature in 30 minutes. ¹HNMR of the reaction mixture sample willshow quantitative conversion. Et₃N is then removed under reducedpressure.

EXAMPLE 16 Preparation of 2-(acetylthiomethyl)hexanal

To a stirred mixture of n-butylacrolein (13.3 ml, 100 mmol) and Et₃N(0.7 mL, 5 mmol) at 0° C. under nitrogen is added thioacetic acid (7.2mL, 100 mmol) in 5 minutes. The mixture is allowed to warm to roomtemperature in 30 minutes. ¹HNMR of the reaction mixture sample willshow quantitative conversion. Et₃N is then removed under reducedpressure.

EXAMPLE 17 Preparation of 2-methyl-3-phenylthiopropanal

To a stirred mixture of 51.4 g (0.733 mole) of methacrolein and 2 g(0.018 mole) of triethylamine at 0-5° C. is added 80.8 g (0.733 mole) ofbenzenethiol slowly. The addition rate is such that the temperature wasunder 10° C. The reaction mixture is stirred at 0-5° C. for one hour.The mixture is placed on a rotary evaporator to remove triethylamine.

EXAMPLE 18 Preparation of 2-(((4-chlorophenyl)sulfonyl)methyl)hexanal

To a stirred solution of 4-chlorobenzosulfinate sodium salt (4.10 g,20.81 mmol) in 20 mL of acetic acid at 60° C. is added 2-butylacrolein(3.8 mL , 28.56 mmol) slowly. The reaction mixture us kept at 50° C. for3.5 hours. The mixture us diluted with 10 mL of water and extracted withethyl acetate (2×10 mL). The combined extract is washed with saturatedNaHCO₃, water, brine, and dried with MgSO₄. After removing solvents, theproduct is obtained as a yellowish slightly viscous oil in 94% yield.

EXAMPLE 19 Preparation of 2-(((4-methylphenyl)sulfonyl)methyl)hexanal

To a stirred solution of 4-toluenesulfinate sodium salt (10.10 g, 56.68mmol) in 35 mL of acetic acid at 50° C., is added 2-butylacrolein (10.6mL, 79.66 mmol) slowly. The reaction mixture is kept at 50° C. for 3hours. After cooling to room temperature, the mixture is diluted with 50mL of water and extracted with ethyl acetate (2×25 mL). The combinedextract is washed with saturated NaHCO₃, water, brine, and dried withMgSO₄. After removing solvents, the product is obtained as a yellowliquid in 75% yield.

EXAMPLE 20 Preparation of (4E)-2-(acetylthiomethyl)-2-butylhex-4-enal

To a stirred solution of 2-(acetylthiomethyl)hexanal (32.6 g, 0.173mole) in 325 ml of xylenes in a 500-mL RBF fitted with a Dean-Stark trapis added 2-hydroxy-3-butene (22.5 mL, 0.259 mole), followed bypyridinium p-toluenesulfonate (4.34 g, 0.017 mole) at room temperatureunder nitrogen. The mixture is heated to reflux overnight. After coolingto room temperature, the xylenes solution is washed with 300 mL ofsaturated NaHCO₃ solution. The aqueous phase is extracted with 300 mL ofethyl acetate. The combined organic extract is washed with 200 mL ofbrine and 200 mL of water. After removing solvents, the product isobtained by vacuum distillation (157-160° C./1.5 mmHg) in 80.5% yield.

EXAMPLE 21 Preparation of (4E)-2-butyl-2-(phenylthiomethyl)hex-4-enal

2-(Phenylthiomethyl)hexanal (2.67 g, 12 mmol), 3-buten-2-ol (5 mL, 58mmol), and p-toluenesulfonic acid (0.05 g, 0.26 mmol) are added to 25 mlof xylenes. The reaction mixture is heated to reflux using a Dean-Starktrap to collect water. After 3 hours, the mixture is cooled to roomtemperature and diluted with ethyl acetate, which is washed saturatedNaHCO₃ solution, brine, and dried with MgSO₄. After removing solvents,the crude product is purified by chromatography. The product is obtainedin 78.6% as a colorless oil.

EXAMPLE 22 Preparation of (4E)-2-methyl-2-(phenylthiomethyl)-hept-4-enal

2-Methyl-3-phenylthiopropanal (9.07 g, 0.05 mole), 1-penten-3-ol (21.67g, 0.25 mole), and p-toluenesulfonic acid (0.24 g, 0.0013 mole) areadded to 90 ml of xylenes. The reaction mixture is heated to refluxusing a Dean-Stark trap to collect water. After 3 hours, the mixture iscooled to room temperature and quenched with 30 ml of saturated NaHCO₃solution. The two phases are separated and the aqueous phase isextracted with 30 ml of ethyl acetate. The combined organic extracts iswashed with 30 ml of brine and dried with Na₂SO₄. After removingsolvents, the crude product is purified by chromatography. The productis obtained in 77% as a colorless oil.

EXAMPLE 23 Preparation of (4E)-2-methyl-2-(phenylthiomethyl)-hex-4-enal

2-Methyl-3-phenylthiopropanal (9.07 g, 0.05 mole), 3-buten-2-ol (18.04g, 0.25 mole), and p-toluenesulfonic acid (0.24 g, 0.0013 mole) areadded to 90 ml of xylenes. The reaction mixture is heated to refluxusing a Dean-Stark trap to collect water. After 3 hours, the mixture iscooled to room temperature and quenched with 30 ml of saturated NaHCO₃solution. The two phases are separated and the aqueous phase isextracted with 30 ml of ethyl acetate. The combined organic extracts iswashed with 20 ml of brine and dried with Na₂SO₄. After removingsolvents, the crude product is purified by chromatography. The productis obtained in 74.3% as a colorless oil.

EXAMPLE 24 Preparation of(4E)-2-butyl-2-(((4-chlorophenyl)sulfonyl)methyl)hex-4-enal

To a stirred solution of 2-(((4-chlorophenyl)-sulfonyl)methyl)hexanal(3.38 g, 11.73 mmol) in 30 ml of toluene in a RBF fitted with aDean-Stark trap is added 2-hydroxy-3-butene (5 mL, 57.73 mmol), followedby p-toluenesulfonic acid (0.13 g) at room temperature under nitrogen.The mixture is heated to reflux for 20 hours. After cooling to roomtemperature, the toluene solution is diluted with 10 mL of ethyl acetateand washed with 10 mL of saturated NaHCO₃ solution. The aqueous phase isextracted with ethyl acetate. The combined organic extract is washedwith water (2×10 mL), brine (1×10 mL), and dried with MgSO₄. Afterremoving solvents, the product is obtained as a brownish oil in 98%yield.

EXAMPLE 25 Preparation of(4E)-2-butyl-2-(((4-methylphenyl)sulfonyl)methyl)hex-4-enal

To a stirred solution of 2-(((4-methylphenyl)-sulfonyl)methyl)hexanal(5.63 g, 21 mmol) in 35 ml of toluene in a RBF fitted with a Dean-Starktrap is added 2-hydroxy-3-butene (10 mL, 115 mmol), followed byp-toluenesulfonic acid (0.13 g) at room temperature under nitrogen. Themixture is heated to reflux overnight. After cooling to roomtemperature, the toluene solution is washed with saturated NaHCO₃solution (2×10 mL), water (2×20 mL), brine (1×20 mL), and dried withMgSO₄. After removing solvents, the product is obtained as a brownishoil in quantitative yield with a GC purity of 89%.

EXAMPLE 26 Preparation of2-butyl-2-(((4-methylphenyl)sulfonyl)methyl)hexanal

To a solution of 0.5 g of2-butyl-2-(((4-ethyl-phenyl)sulfonyl)methyl)hexanal in 30 mL of tolueneis added mL of 37% formaldehyde and 220 mg of 20% Pd(OH)₂/C catalyst.The reaction mixture is purged with dry nitrogen gas (3×) and hydrogengas (3×) and hydrogenated at 60 psi H2 and 60° C. for 15 hours. Thecatalyst is removed by filtration and washed with ethanol (2×20 mL).Solvents of the combined washes and filtrate are removed under vacuum toyield the crude product.

For the following examples ¹H and ¹³C NMR spectra were recorded on aVarian 300 spectrometer at 300 and 75 MHz respectively. The ¹H chemicalshifts are reported in ppm downfield from tetramethylsilane. The ¹³Cchemical shifts are reported in ppm relative to the center line of CDCl₃(77.0 ppm). Melting points were recorded on a Buchi 510 melting pointapparatus and are uncorrected. HPLC data was obtained on a SpectraPhysics 8800 Chromatograph using a Beckman Ultrasphere C18 250×4.6 mmcolumn. HPLC conditions: detector wavelength=254 nm, sample size=10 μL,flowrate=1.0 mL/min, mobile phase=(A) 0.1% aqueous trifluoroacetic acid:(B) acetonitrile. Quantitative HPLC analysis was determined by runningsamples of known concentration of the crude product and of purifiedproduct, adjusting the peak areas for concentration differences, anddividing the peak area of the crude sample by the peak area of thepurified sample. HPLC Gradient:

Time % A % B  0 min 50  50  5 min 50  50 30 min  0 100 40 min  0 100

EXAMPLE 27 Preparation of Compound 32

Procedure A: Na₂S.9H₂O (8.64 g, 36.0 mmol) and sulfur (1.16 g, 36.0mmol) were combined in a 50 mL round-bottom flask. The mixture washeated to 50° C. until homogeneous, and water (10.0 mL) was added.Compound 33 (10.00 g, 36.0 mmol) and ethanol (100 mL) were combined in a500 mL round-bottom flask. The reaction flask was purged with N₂ andequipped with mechanical stirrer. The reaction mixture was heated to 65°C. until homogeneous, and then increased to 74° C. The disulfidesolution was added to the 500 mL reaction flask over 10 minutes. After1.5 hrs at reflux, analysis of an aliquot by HPLC indicated completeconversion of 33. Aqueous 18% NaOH (20.0 g, 90.0 mmol) was added over 5minutes (endothermic). After 15 minutes, the reaction mixture was cooledto 0° C., and 30% H₂O₂ (16.00 g, 140.0 mmol) was added dropwise keepingtemp below 20° C. After 1.5 hrs at <20° C., analysis of an aliquot byHPLC indicated total oxidation of the sodium thiophenolate intermediate.The ethanol was removed under reduced pressure at <65° C. Water (100 mL)was added, and the mixture was washed with CH₂Cl₂ (100 mL). 10% HCl (˜40mL) was added until pH=1, and the reaction mixture was extracted withCH₂Cl₂ (100.0 mL). 2-Butylacrolein (5.20 mL, 39.2 mmol) was added to theorganic extract, and the mixture was stirred for 1 hour. Analysis of analiquot by HPLC indicated very little sulfinic acid intermediate. Theorganic layer was concentrated in vacuo to give an amber solid (14.19g). Analysis by quantitative HPLC indicated 84% purity, whichcorresponds to 11.92 g Michael adduct (79% yield of 32 based on 33).

Procedure B: Compound 33 (4.994 g, 17.98 mmol) and dimethylacetamide(21.0 mL) were combined in a dry 250 mL round-bottom flask. The reactionflask was purged with N₂, equipped with magnetic stirrer, and heated to40° C. until the mixture became homogeneous. Na₂S.3H₂O (2.91 g, 22.37mmol) and water (4.0 mL) were combined in a separate flask and heated to55° C. until homogeneous. The Na₂S solution was then added portion-wiseto the reaction flask over 25 minutes. After 2.5 hrs at 40° C., analysisof an aliquot by HPLC indicated complete conversion of 33. After 2 hrsmore, the reaction mixture was cooled to 30° C., and aq. 18% NaOH (10.02g, 44.90 mmol) was added. After 20 min, the reaction mixture was cooledto 0° C., and 30% H₂O₂ (8.02 g, 70.6 mmol) was added dropwise over 30minutes while maintaining a temperature of less than 15° C. After 10min, an aliquot was removed and analyzed by HPLC, which indicated >93%oxidation of the sodium thiophenolate intermediate. After 1 hr, Na₂SO₃(6.05 g, 48.0 mmol) and water (50.0 mL) were added, and the cooling bathwas removed. After 20 min, the mixture was washed with toluene (orCH₂Cl₂) (2×50.0 mL). Toluene (or CH₂Cl₂) (50.0 mL), 2-butylacrolein(2.60 mL, 19.6 mmol), and n-Bu₄NI (0.032 g, 0.087 mmol) were added, andthe reaction mixture was cooled to 0° C. To this, 10% HCl (˜30 mL) wasadded until pH=1. The cooling bath was removed, and the reaction mixturewas stirred for 30 min. Analysis of an aliquot of the aqueous layer byHPLC indicated very little sulfinic acid intermediate. After 30 minmore, the aqueous layer was separated and discarded. The organic layerwas kept at −10° C. overnight, stirred at R.T. for 5 hrs. Analysis ofthe toluene solution by quantitative HPLC indicated 6.444 g Michaeladduct, (85% yield of 32 based on 33).

For characterization, a portion of the crude product was concentrated invacuo and precipitated from ethyl ether to afford a yellow solid: mp62.0-76.0° C.; HPLC (CH₃CN/H₂O): rt=22.4 min. ¹H NMR (CDCl₃) ????????t,J=6.0 Hz 3H), 1.24 (m, 4H), 1.53 (m, 1H), 1.70 (m, 1H), 2.83 (dd,J=14.1, 4.2 Hz, 1H), 2.98 (m, 1H), 3.56 (dd, J=14.4, 7.8 Hz, 1H), 3.79(s, 3H), 4.53 (s, 2H), 6.87 (dd, J=6.6, 2.4 Hz, 2H), 7.13 (d, J=8.7 Hz,2H), 8.12 (s, 1H), 8.20 (d, J=1.2 Hz, 2H), 9.53 (d, J=0.9 Hz, 1H). ¹³CNMR (CDCl₃) ? 13.6, 22.4, 28.1, 28.5, 37.4, 45.4, 53.9, 55.2, 114.4,121.7, 127.3, 129.6, 130.3, 132.1, 142.7, 144.1, 150.7, 158.7, 199.5.HRMS (ES+) calcd for C₂₁H₂₅NO₆S+NH₄: 437.1731, found: 437.1746. Anal.(C₂₁H₂₅NO₆S): C, 60.13; H, 6.01; N, 3.34; O, 22.88; S, 7.64. Found: C,60.22; H, 5.98; N, 3.32; O, 22.77; S, 7.73.

EXAMPLE 28 Preparation of Compound 18a

Procedure A: Compound 32 (11.577 g, 27.598 mmol), p-toluenesulfonic acidmonohydrate (0.6115 g, 3.21 mmol), CH₂Cl₂ (70 ml) and 3-buten-2-ol(13.91 mL, 160.5 mmol) were combined in a dry 250 mL round-bottom flask.The reaction flask was purged with N₂ and equipped with magneticstirrer, Dean Stark trap, and reflux condenser. The reaction mixture washeated to reflux. After 10.25 hrs, analysis of an aliquot by HPLCindicated 78.6% 18a, 13.3% pre-Claisen enol ether, 3.7% 32 andapproximately 4% byproducts. K₂CO₃ (1.50 g, 10.8 mmol) was added to thereaction flask. After 2.5 hrs, CH₂Cl₂ (50.0 mL ) was added, and themixture was filtered through celite. The filtrate was collected andconcentrated in vacuo to yield an amber oil (15.73 g). Quantitative HPLCwas performed using a sample of purified 18a. The total peak area of thecrude product was determined by summing the pre-Claisen enol ether and18a peaks. It was assumed that they have the same HPLC response factors.Analysis by quantitative HPLC indicated 90% purity, which corresponds to14.20 g 18a and pre-Claisen enol ether 47, (94% yield of 18a based on32).

Procedure B: Compound 32 (5.43 g, 12.9 mmol), 3-buten-2-ol (76.16 g,85.4 mmol), p-toluenesulfonic acid monohydrate (0.258 g, 1.36 mmol) andtoluene (51.0 mL) were combined in a 100 mL round-bottom flask. Thereaction flask was purged with N₂ and equipped with magnetic stirrer,Dean Stark trap, condenser, and vacuum line. The condenser was cooled to−10° C. via a Cryocool bath, and the Dean Stark trap was filled with3-buten-2-ol (about 11 mL). The reaction flask was evacuated to 107.5mmHg via a pressure controller and heated to 49° C. After 4 hrs, thereaction flask was cooled to R.T. and concentrated in vacuo at 30° C.The crude product was collected as an amber oil (8.154 g). QuantitativeHPLC was performed using a sample of purified 18a. The total peak areaof the crude product was determined by summing the pre-Claisen enolether and 18a peaks. It was assumed that they have the same HPLCresponse factors. Analysis by quantitative HPLC indicated 69% purity,which corresponds to 5.626 g 18a and pre-Claisen enol ether 47, (80%yield of 18a based on 32)): HPLC (CH₃CN/H₂O): 18a: rt=32.56, 32.99,33.09 min, pre-Claisen enol ether: rt=30.7 min. ¹H NMR (CDCl₃)?0.84-0.93 (m, 3H), 1.09-1.34 (m, 10H), 1.40-1.70 (m, 2H), 2.16-2.35 (m,1H), 2.88-2.98 (m, 1H), 3.52-3.63 (m, 1H), 3.80 (m, 3H), 3.84-4.10 (m,2H), 4.49 (s, 1H), 4.50 (s, 1H), 4.59 (d, J=3.0 Hz, 0.25H), 4.60 (d,J=2.7 Hz, 0.25H), 4.65 (d, J=2.4 Hz, 0.25H), 4.70 (d, J=2.4 Hz, 0.25H),5.00-5.18 (m, 4H), 5.42-5.84 (m, 2H), 6.87 (d, J=8.7 Hz, 1H), 6.88 (d,J=8.4 Hz, 1H), 7.12-7.17 (m, 2H), 8.02 (t, J=2.4 Hz, 1H), 8.14-8.17 (m,1H), 8.23-8.27 (m, 1H); ¹³C NMR (CDCl₃) ??13.8, 20.1, 20.9, 21.0, 21.4,21.51, 21.57, 21.6, 22.53, 22.55, 22.57, 28.7, 28.8, 28.94, 28.99, 29.0,29.3, 29.4, 29.8, 37.1, 37.2, 37.3, 38.73, 38.75, 53.3, 55.2, 55.60,55.66, 55.7, 55.9, 73.4, 73.5, 73.8, 73.9, 74.3, 75.1, 75.9, 97.7, 98.3,98.4, 99.5, 113.6, 114.4, 114.5, 114.9, 115.7, 115.9, 116.1, 116.3,116.7, 116.9, 121.22, 121.26, 121.31, 121.34, 126.70, 126.75, 126.8,129.73, 129.77, 130.45, 130.48, 130.5, 131.51, 131.51, 131.57, 139.6,139.8, 139.9, 140.1, 140.2, 140.3, 143.6, 143.70, 143.71, 143.81,143.84, 144.26, 144.29, 144.34, 144.35, 144.37, 150.5, 158.6; HRMS (ES+)calcd for C₂₉H₃₉NO₇S+NH₄: 563.2791, found: 563.2804.

EXAMPLE 29 Preparation of Compound 31

Procedure A: A crude mixture of 18a and pre-Claisen enol ether 47(13.636 g, 24.989 mmol), o-xylene (75.0 mL), and calcium hydride (0.334g, 7.93 mmol) were combined in a dry 250 mL round-bottom flask. Thereaction flask was purged with N₂, equipped with magnetic stirrer, andheated to 145° C. After 3 hours, an aliquot was removed and analyzed byHPLC, which indicated 93% 31, 1% 32, 3% pre-Claisen enol ether 47, and4% byproducts. The reaction mixture was cooled to RT and filteredthrough celite washing with o-xylene (50.0 mL). The crude product wasconcentrated in vacuo and collected as an amber oil (11.525 g). Analysisby quantitative HPLC indicated 86% purity, which corresponds to 9.9115 gClaisen product (80% yield based on the mixture of 31 and pre-Claisenenol ether 47).

Procedure B: A crude mixture of 18a and pre-Claisen enol ether 47 (2.700g, 4.948 mmol), toluene (15.0 mL) and calcium hydride (0.0704 g, 1.67mmol) were combined in a dry Fischer-Porter bottle. The reaction flaskwas purged with N₂, equipped with magnetic stirrer, and heated to 145°C. After 10 hours, analysis of an aliquot by HPLC indicated 90.9%Claisen product 31), 2.8% pre-Claisen enol ether 47, 1.3% 18a and 5%byproducts. Toluene (30.0 mL) was then added, and the mixture wasfiltered through celite. Concentration in vacuo of the filtrate affordedthe crude product as an amber oil (2.6563 g). Analysis by quantitativeHPLC indicated 82% purity, which corresponds to 2.1782 g Claisen product31, (93% yield based on the mixture of 18a and pre-Claisen enol ether47).

Procedure C: Purified 18a (0.228 g, 0.417 mmol) was placed in a 100 mLround-bottom flask. The reaction flask was placed in a Kugelrohrapparatus and evacuated to 100 mtorr. After 1 hr, the apparatus washeated to 40° C. After 15 minutes more, the apparatus was heated to 145°C. After 1 hr, the apparatus was cooled to R.T. to afford an dark oil(0.171 g). Analysis by HPLC indicated 88% Claisen product 31, 3%pre-Claisen enol ether 47, 3% 18a and 6% byproducts. This corresponds toan 81% yield based on 18a. Quantitative HPLC was not performed.

For characterization, a portion of the residue was purified by flashcolumn chromatography on silica gel (eluting with EtOAc/hexanes),concentrated in vacuo, and the desired product was collected as an amberoil: HPLC(CH₃CN/H₂O): rt=29.1 min. ¹H NMR (CDCl₃) ??0.88 (t, J=6.9 Hz,3H), 1.06 (m, 1H), 1.17-1.34 (m, 3H), 1.61 (d, J=6.3 Hz, 3H), 1.68 (m,1H), 1.83-1.93 (m, 1H), 2.42 (dd, J=14.4, 6.6 Hz, 1H), 2.63 (dd, J=14.7,8.1 Hz, 1H), 3.12 (s, 2H), 3.80 (s, 3H), 4.52 (ABq, 2H), 5.16-5.26 (m,1H), 5.52-5.64 (m, 1H), 6.88 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H),8.09 (s, 1H), 8.21 (s, 1H), 8.22 (s, 1H), 9.40 (s, 1H)?? ¹³C NMR (CDCl₃)?13.7, 17.9, 22.8, 25.6, 32.6, 35.9, 37.2, 52.6, 55.1, 57.2, 114.4,121.7, 123.4, 127.1, 129.8, 130.2, 131.2, 131.5, 143.7, 144.5, 150.5,158.7, 202.5. HRMS (ES+) calcd for C₂₅H₃₁NO₆S+NH₄: 491.2216, found:491.2192. Anal. (C₂₅H₃₁NO₆S): C, 63.40; H, 6.60; N, 2.96; O, 20.27; S,6.77. Found: C, 63.36; H, 6.39; N, 3.05; O, 20.59; S, 6.71.

Other Reactions to Form Claisen Product 31

General procedure for other reactions of acetal to: In a typicalreaction, the purified acetal 18a is combined with solvent, base andwater removing agent (if indicated and heated. The zeolites andmolecular sieves are activated at 300° C. The reported conversion isbased on the peak area of 31 vs. 18a in the HPLC data. The reportedyield is based on the peak area of the products vs. byproducts in theHPLC data. The results are summarized below.

Example No. Base/Conditions Results 30 100° C. 95% conv./32% yield @ 4hrs. 31 4 A sieves/o-xylene/145° C. 6% conv./39% yield @ 5 hrs. 32o-xylene/120° C. 100% conv./58% yield @ 2.5 33 o-xylene/145° C. 100%conv./70% yield @ 2 hrs. 34 CH₃CN/140° C. 0% conv. @ 6 hrs. 35 PPTS(0.1eq.)/pyr.(0.15 eq.)/o- 84% conv./74% yield @ 3 hrs. xylene/120° C. 36PPTS(0.13 eq.)/4 A sieves/o- 21% conv./74% yield @ 1 hrs. xylene/120° C.37 pyr.(9.0 eq.)/CH₃CN/140° C. 0% conv. @ 2.5 hrs. 38 pyr.(12.3eq.)/xylenes/140° C. 1% conv./100% yield @ 2 hrs. 39 Et₃N(0.3eq.)/o-xylene/145° C. 19% conv./78% yield @ 6 hrs. 40 CaH₂(0.46 eq.)/4 Asieves/o- 97% conv./92% yield @ 5 hrs. xylene/145° C. 41 CaH₂(0.3eq.)/PhCH₃/145° C. 96% conv./95% yield @ 10 hrs. 42 CaH₂(0.43eq.)/PTSA(0.07 eq.)/4 A 100% conv./34% yield @ 1 sieves/o-xylene/145° C.hrs. 43 CaH₂(0.42 eq.)/4 A 0.2% conv./11% yield @ 8 hrs.sieves/CH₂Cl₂/145° C. 44 PhCH₃/prefilter through basic 98% conv./79%yield @ 3.5 alumina/145° C. hrs. 45 AlCl₃(2.0 eq.)/Et₃N(4.1 0% conv. @ 4hrs. eq.)/THF/25° C. 46 Pd(PhCN)₂Cl₂ (0.1 eq.)/THF/25° C. reversion to32. 47 BF₃.OEt₂(1.2 eq.)/CH₂Cl₂/−50° C. reversion to 32. 48HMDS/TMSI/CH₂Cl₂/25° C. 0% conv. @ 5 hrs.

Other Reactions to Form Acetal 18a and the Pre-Claisen Enol Ether 47

General procedure: In a typical reaction, the sulfone aldehyde 32 iscombined with 3-buten-2-ol (about to about 50 eq.), solvent and acidsource indicated. If indicated, 4 A molecular sieves (50 wt %), andtrimethyl orthoformate TMOF (1.2 eq.) are added to the reaction flask.If no solvent is indicated, 3-buten-2-ol is the solvent. The zeolitesand molecular sieves are activated at 300° C. The observed products area mixture of the acetal 18a and the pre-Claisen enol ether, asdetermined by LCMS and NMR. The reported conversion is based on the peakarea of product(s) vs. 32 in the HPLC data. The reported yield is basedon the peak area of the products vs. byproducts in the HPLC data. Theresults are summarized below.

Example No. Acid/Conditions Results 49 TFA(0.24 eq.)/CH₃CN/4 Å 2.5%conv./50% yield @ 18 sieves/25° C. hrs. 50 TFA(3.5 eq.)/4 A sieves/50°C. 42% conv./74% yield @ 4.5 hrs. 51 TFA(3.8 eq.)/Isopropenylacetate(3.3 44% conv./95% yield @ eq.)/50° C. 2 hrs. 52 TFA(3.5 eq.)/65°C. 68% conv./86% yield @ 5.5 hrs. 53 TEA(3.0 eq.)/90° C. 73% conv./75%yield @ 5.5 hrs. 54 TFA(3.0 eq.)/PhCH₃/4 Å 90% conv./53% yield @ 58 hrs.sieves/TMOF/120° C. 55 TFA(3.0 eq.)/CH₃CN/4 Å 92% conv./58% yield @ 41hrs. sieves/TMOF/120° C. 56 PTSA(0.1 eq.)/25° C. 78% conv./100% yield @16 hrs. 57 PTSA(0.1 eq.)/4 Å sieves/50° C. 87% conv.199% yield @ 2 hrs.58 PTSA(0.1 eq.)/4 Å sieves/70° C. 95% conv./92% yield @ 5.75 hrs. 59PTSA(0.1 eq.)/4 Å sieves/90° C. 87% conv./74% yield @ 2 hrs. 60 PTSA(0.1eq.)/Isopropenyl acetate (3.3 63% conv./94% yield @ 2.5 eg.)/50° C. hrs.61 PTSA(0.12 eq.)/Isopropenyl acetate 83% conv./91% yield @ (3.2eg.)190° C. 1 hrs. 62 PTSA(0.1 eq.)/PhCH₃/4 Å 29% conv./70% yield @ 18his. sieves/TMOF/90° C. 63 PTSA(0.3eq.)/PhCH₃/4 Å 37% conv./70% yield @70 his. sieves/TMOF/120° C. 64 PTSA(0.1 eq.)/PhCH₃/49° C. @ 95%conv./93% yield @ 3.5 107.5 mmHg hrs. 65 PTSA(0.1 eq.)/o-xylene/4 Å 92%conv./96% yield @ 3.5 sieves/50° C. hrs. 66 PTSA(0.1 eq.)/o-xylene/50°C. 59% conv./58% yield @ 7.5 hrs. 67 PTSA(0.1 eq.)/CH₂Cl₂/4 Å 95%conv./100% yield @ 3.5 sieves/47° C. hrs. 68 PTSA(0.05 eq.)/CH₂Cl₂/4 Å95% conv./99% yield @ sieves/47° C. 5 hrs. 69 PTSA(0.025 eq.)/CH₂Cl₂/4 Å15% conv./91% yield @ 6.5 sieves/47° C. hrs. 70 PTSA(0.1 eq.)/CH₂Cl₂/47°C. 100% conv./96% yield @ 1 hrs. 71 PTSA(0.1 eq.)/EtOAc/90° C. 75%conv./85% yield @ 5 hrs. 72 PTSA(0.1 eq.)/EtOAc/4 Å sieves/50° C. 44%conv./85% yield @ 1.5 hrs. 73 PTSA(0.1 eq.)/iPrOAc/4 Å sieves/50° C. 62%conv./93% yield @ 6 hrs. 74 PTSA(0.1 eq.)/BuOAc/4 Å sieves/50° C. 72%conv./69% yield @ 6 hrs. 75 PTSA(0.1 eq.)/THF/4 Å 63% conv./94% yield @sieves/50° C. 7 hrs. 76 PTSA(0.24 eq.)/CH₃CN/4 Å sieves/25° C. 85%conv./100% yield @ 19 hrs. 77 PTSA(0.1 eq.)/MIBK/4 Å sieves/50° C. 59%conv./95% yield @ 3 hrs. 78 PTSA(0.1 eq.)/PhCF₃/50° C. 55% conv./65%yield @ 4 hrs. 79 PTSA(0.15 eq.)/Pd(PhCN)₂Cl₂ 100% conv./97% yield @(0.09 eg.)/4 Å sieves/25° C. 23 hrs. 80 PPTS(0. 1 eq.)/4 Å sieves/ 65%conv./87% yield @ 90° C. 7.5 hrs. 81 CBV 5020 zeolites(25 wt %)/CH₃CN/2530% conv./97% yield @ 22 hris. 82 CBV 5020 zeolites(25 wt %)/ 81%conv./99% yield @ 4 Å sieves/50° C. 2 hrs. 83 CBV 5020 zeolites(25 wt%)/ 66% conv./94% yield @ 4 Å sieves/70° C. 24 hrs. 84 CBV 5020zeolites(25 wt %)/ 81% conv./98% yield @ 4 Å sieves/90° C. 1 hrs. 85 CBV5020 zeolites(25 wt %)/ 71% conv./93% yield @ 90° C. 2 hrs 86 CBV 5020zeolites(25 wt %)/Isopro- 79% conv./91% yield @ penyl acetate (3.0eg.)190° C. 1.5 hrs. 87 CBV 5020 zeolites(10 wt %)/PhCH₃/4 Å 40%conv./53% yield @ sieves/TMOF/ 21 hrs. 120° C. 88 300WN0030 gzeolites(10 wt %)/PhCH₃/4 22% conv./57% yield @ sieves/ 21 hrs.TMOF/120° C. 89 Montmorillonite K10(10 wt. %)/PhCH₃/4 70% conv./64%yield @ sieves/TMOF/120° C. 57 hrs. 90 Montmorillonite K10(20 wt %)/ 4%conv./99% yield @ 4 Å sieves/25° C. 18 hrs. 91 Montmorillonite K10(20 wt%)/CH₃CN/ 4% conv./99% yield @ sieves/25° C. 21 hrs. 92 Amberlyst 15(20wt. %)/ 49% conv./96% yield @ CH₂Cl₂/4 Å sieves/47° C. 2 hrs. 93 Aceticacid(0.24 eq.)/ 0% conv./0% yield @ CH₃CN/4 Å sieves/25° C. 22 hrs. 94Acetic acid(3.0 eq.)/90° C. 15% conv./78% yield @ 2.5 hrs. 95 Aceticacid (3.0 eq.)/4 Å sieves/90° C. 79% conv./84% yield @ 6.5 hrs. 96 HCl(0.20 eq.)/25° C. 3% conv./6% yield @ 1 hrs. 97 HCl (4.1 eq.)/4 Åsieves/ 87% conv./98% yield @ 25° C. 2.5 hrs. 98 HCl (1.1 eq.)/dioxane/4Å sieves/25° C. 67% conv./100% yield @ 1 hrs. 99 HCl (1.1 eq.)/CH₂Cl₂/4Å sieves/47° C. 69% conv./100% yield @ 1 hrs. 100  AlClEt₂/(0.16 eq.)/4Å sieves/25° C. 80% conv./59% yield @ 47 hrs. 101  Pd(PPh₃)₄ (0.10eq.)/4 Å sieves/25° C. retro-Michael reaction only 102  Pd(PhCN)₂Cl₂(0.10 eq.)/ 5% conv./47% yield @ TIHF/4 Å sieves/25° C. 4.5 hrs. 103 Pd(PhCN)₂Cl₂ (0.12 eq.)/ 63% conv./100% yield @ 4 Å sieves/25° C. 2 hrs.

EXAMPLE 104 Preparation of Compound 29

To a solution of 0.434 g of compound 31 in 30 mL of hot ethanol wasadded 5 mL of 37% formaldehyde and 220 mg of 20% Pd(OH)₂/C catalyst. Thereaction mixture was purged with nitrogen gas (3×) and H₂ (3×) andhydrogenated at 60 psi and 60° C. for 15 hours. The catalyst was removedby filtration and washed with ethanol (2×20 mL). Solvents of thecombined washes and filtrate were removed to yield 370 mg of crude 29(85%). An analytical sample was obtained by recrystallization fromethanol and water.

EXAMPLE 105 Preparation of Compound 12c

A 1L 3-neck jacked flask is fitted with baffles, a bottom valve, anoverhead stirred, an addition funnel, and a Neslab cooling bath. To thereactor is charged 35 grams of potassium thioacetate. The reactor isflushed with nitrogen gas and to it is charged 85 mL ofdimethylformamide (DMF). Mixing is started at 180 rpm and the bath iscooled to 18° C. The reactor is again flushed with nitrogen gas and toit is added 73.9 grams of compound 53 over 20 minutes via a droppingfunnel. The pot temperature is maintained at 23° C. during the addition.The mixture is stirred for 1 hour at about 23° C. to 27° C. To themixture is then added 80 mL of water followed by 100 mL of ethylacetate. The mixture is stirred for 20 minutes. The layers are allowedto separate and the aqueous layer is drained off. To the pot is addedanother 50 mL of water and the mixture is stirred for 15 minutes. Thelayers are separated and the aqueous layer is drained off. Then to thepot is added 50 mL of brine and the mixture is stirred for another 15minutes. The layers are separated and the aqueous layer is removed. Theorganic layer is concentrated under reduced pressure (water aspiratorpressure) at 47° C. to obtain 68.0 grams of orange oily compound 12c.

EXAMPLE 106 Preparation of Diethyl Acetal Compound 12d

A 250 mL 3-neck round bottom flask is fitted with an overhead stirrer, aTeflon coated temperature probe, and a separatory funnel. To the flaskis charged 78 g of compound 12c and 200 mL of ethanol. The reactor isflushed with nitrogen gas and to it is charged 60 mL oftriethylorthoformate. Then to the flask is added 4 grams ofp-toluenesulfonic acid. The mixture is stirred at room temperature for16 hours. The mixture is then concentrated under reduced pressure and tothe flask is added 100 mL of ethyl acetate. Next is added 1.7 grams ofsodium bicarbonate in 50 mL of water. The mixture is stirred for 3minutes. The layers are allowed to separate and the aqueous layer isdrained. The organic layer is filtered through a pad of sodium sulfateand the organic layer is concentrated under reduced pressure (wateraspirator pressure) to afford 96.42 grams of orange oily compound 12d.

EXAMPLE 107 Preparation of Diethyl Acetal Compound 67

A 0.5 L 3-neck jacked flask is fitted with baffles, a bottom valve, anoverhead stirrer, an addition funnel, a nitrogen inlet, a silicon oilbubbler, a Teflon-coated temperature probe, and a PolySciencecooling/heating bath. To the flask is charged 48.85 grams of compound33. The flask is flushed with nitrogen gas and to it is charged 75 mL ofDMSO. The mixture is again flushed with nitrogen and agitation is begun.The jacket temperature is set at 40° C. and to the flask is added 56.13grams of compound 12d. Stirring is continued for 30 minutes and to themixture is slowly added 28 mL of 50% aqueous NaOH over 120 minutes via adropping funnel. The mixture is stirred for 3 hours while maintainingthe jacket temperature at 40° C. The reaction is allowed to cool toambient temperature and the mixture is stirred for 15 hours (overnight).The jacket temperature is then adjusted to 5° C. and to the mixture isslowly added 300 mL of water. The reaction is exothermic. The biphasicmixture is transferred to a separatory funnel and the mixture isextracted with 2×150 mL of ethyl acetate. The layers were allowed toseparate for 30 minutes and the aqueous layer was drained off. The ethylacetate layers are combined. The combined ethyl acetate mixture isextracted successively with 400 mL and 100 mL of water. If the layers donot readily separate within 30 minutes, 50 mL of brine may be added tothe mixture to aid in separation of the layers. The aqueous layer isdrained off. The ethyl acetate layer is then extracted with 100 mL ofbrine. The ethyl acetate layer is then dried over anhydrous magnesiumsulfate and the solids are filtered off through a plug of activatedcharcoal/Supercel Hyflow. The filtrate is concentrated under reducedpressure and dried under vacuum for 18 hours to obtain 91.98 grams of anorange-brown, viscous oil (compound 67).

EXAMPLE 108 Conversion of Diethyl Acetal Compound 67 to1-(2,2-Dibutyl-3-oxopropylsulfonyl)-2-((4-methoxyphenyl)methyl)benzene(29)

Compound 67 (36 grams dissolved in 122 mL of ethyl acetate), 300 mLacetic acid, 27.3 g of 37 wt % formaldehyde, and 50 mL of water arecharged into a 500 mL 1-neck round bottom flask in a Parr Shaker. To themixture is added 7.4 grams of 5% Pd/C (dry basis, Johnson Mathey). Thereactor is purged three times with nitrogen gas and then purged threetimes with hydrogen gas. The reactor is pressurized to 60 psi and heatedto 60° C. The temperature and pressure are held for 16 hours after whichtime the reactor is allowed to cool to room temperature. The reactionmixture is filtered through a pad of solka flock on a course frittedglass filter. The cake is washed twice with 40 mL of acetic acid andconcentrated to dryness under reduced pressure. The solid is mixed with100 mL ethanol and heated to 80° C. until all the solid is dissolved. Tothis is added 20 mL of tap water to form a homogeneous solution. Themixture is cooled to room temperature and to it is added 3 mL of ethylacetate. A white slurry forms. The slurry is heated to 60° C. until ahomogeneous solution forms. The mixture is cooled to room temperatureand held for two hours. During this time compound 29 crystallizes. Thesolids are filtered through a coarse fritted glass filter. The cake iswashed twice with 40 mL of a 20% (V/V) ethanol in water solution. Thecake is dried at 40-50° C. in a vacuum oven until no weight loss isobserved.

EXAMPLE 109 Preparation of 2-(Acetylthiomethyl)-2-butyl-4-hexenalethylene glycol acetal, 74

Step 1. Preparation of 2-(Acetylthiomethyl)hexanal, 72

A 1 L 3-neck round bottom flask is fitted with a magnetic stir bar, anitrogen inlet, a thermometer probe connected to a temperature monitor,a 50 mL addition funnel, and an ice-water bath. Into the flask ischarged 37.0 mL of thiol acetic acid and the flask contents are cooledto 0-5° C. in the ice-water bath. To the flask is then charged 69.0 mLof butylacrolein via the addition funnel over 2 minutes. The temperatureincreases to a maximum of about 21° C. The reaction is cooled then toabout 10° C. and the flask is charged with 0.72 mL of triethylamine. Thetemperature increases to about 57° C. within about one minute. Stirringcontinues until the temperature drops to about 15° C. The resultingproduct mixture contains compound 72.

Step 2. Preparation of 2-(Acetylthiomethyl)-2-butyl-4-hexenal, 73

The apparatus of Step 1 of this example is further fitted with aDean-Stark trap and a cold water condenser. The reaction flask,containing the product mixture of Step 1, is further charged with 50.0mL of 3-buten-2-ol, 1.987 g of p-toluenesulfonic acid monohydrate, and600 mL of toluene. The mixture is heated to about 105-110° C. withstirring for about 24 hours. During this time water, as well as some3-buten-2-ol and toluene collect in the Dean-Stark trap. The reaction iscomplete when no more water distills over. If desired, an additional 0.5equivalents of 3-buten-2-ol can be added to the flask to make up forloss from distillation. The mixture is allowed to cool to ambienttemperature. The resulting aldehyde mixture contains compound 73.

Step 3. Preparation of 2-(Acetylthiomethyl)-2-butyl-4-hexenal ethyleneglycol acetal, 74

The apparatus and resulting aldehyde mixture of Step 2 of this exampleare further charged with 31.0 mL of ethylene glycol. The mixture isheated with stirring to 105-110° C. for 2 hours. Water and toluenecollect in the Dean-Stark trap during this time. The reaction iscomplete when no more water distills over. The mixture is cooled toambient temperature and the reaction mixture is washed successively with100 mL of saturated sodium bicarbonate aqueous solution, 100 mL ofwater, and 100 mL of brine. The solvent is removed by evaporation in arotary evaporator. The yield is 149 grams of compound 74.

EXAMPLE 110 Preparation of Compound 67

Step 1. Preparation of 2-(Acetylthiomethyl)-2-butyl-4-hexenal diethylacetal, 75

A 250 mL 3-neck round bottom flask is fitted with an overhead stirrer, aTeflon coated temperature probe, and a separatory funnel. To the flaskis charged 78 g of compound 74 and 200 mL of ethanol. The reactor isflushed with nitrogen gas and to it is charged 60 mL oftriethylorthoformate. Then to the flask is added 4 grams ofp-toluenesulfonic acid. The mixture is stirred at room temperature for16 hours. The mixture is then concentrated under reduced pressure and tothe flask is added 100 mL of ethyl acetate. Next is added 1.7 grams ofsodium bicarbonate in 50 mL of water. The mixture is stirred for 3minutes. The layers are allowed to separate and the aqueous layer isdrained. The organic layer is filtered through a pad of sodium sulfateand the organic layer is concentrated under reduced pressure (wateraspirator pressure) to afford compound 75.

Step 2. Preparation of 2-butyl-2-(thiomethyl)hexanal diethyl acetal, 76

A 500 mL 3-neck round bottom flask is fitted with a condenser, amagnetic stir bar, a nitrogen inlet, a thermocouple connected to atemperature controller, and a heating mantle. The flask is purged withnitrogen gas and charged with 19.2 grams of compound 75, 96 mL ofN-methyl pyrrolidone (NMP), 28.3 grams (2.5 equiv.) of p-toluenesulfonylhydrazide, and 18 mL (3.0 equiv.) of piperidine. While stirring, themixture is warmed to about 100° C. for 2 hours. The temperature is keptbelow 107° C. by removing the heat, if necessary. The mixture is cooledto ambient temperature. The product mixture contains compound 76. Ifdesired, this reaction can be run using 2.5 equiv. of p-toluenesulfonylhydrazide and 2.5 equiv. of piperidine.

Step 3. Preparation of Compound 67

The equipment and product mixture of Step 2 of this example are used inthis step. To the flask containing the product mixture of Step 2 ischarged 13.46 grams of compound 33 and 11.2 mL of 50% (w/w) aqueousNaOH. The mixture is heated to 100° C. with mixing and held at thattemperature for 2.5 hours. The mixture is cooled to ambient temperatureand to the flask is added 100 mL of ethyl acetate. This mixture iswashed with 100 mL of water. The aqueous layer is separated and washedwith 100 mL of ethyl acetate. The ethyl acetate layers are combined andwashed in succession with 3×100 mL of water and with 2×50 mL of brine.The organic layer is dried over magnesium sulfate and the solvent isremoved under vacuum in a rotary evaporator. The yield is 26 grams ofcompound 67 as a reddish brown oil.

EXAMPLE 111 Differential Scanning Calorimetry (DSC)

DSC experiments are performed either on a Perkin Elmer Pyris 7Differential Scanning Calorimeter or on a TA Instruments DifferentialScanning Calorimeter with 5-10 mg samples hermetically sealed in astandard aluminum pan (40 microliters) with a single hole punched in thelid. An empty pan of the same type is used as a reference. The heatingrate is 10° C./min with dry nitrogen purge. FIG. 9 shows typical DSCthermograms for Form I (plot(a)) and Form II (plot(b)) of compound 41.

EXAMPLE 112 X-Ray Powder Diffraction Patterns

X-ray powder diffraction experiments are conducted on an Ineltheta/theta diffraction system equipped with a 2 kW normal focus X-raytube (copper). X-ray scatter data are collected from 0 to 80° 2 theta.Samples are run in bulk configuration. Data are collected and analyzedon a Dell computer running Inel's software. In at least one case,samples are placed in a glass capillary tube and ends are sealed toprevent loss of solvent. The capillary is mounted on a special adapterin the path of the X-ray beam and data were collected.

Alternatively, the X-ray diffraction experiments are conducted on asystem comprising a Siemens D5000 diffraction system equipped with a 2kW normal focus X-ray tube (copper). The system is equipped with anautosampler system with a theta-theta sample orientation. Datacollection and analysis is performed on a MS-Windows computer withSiemens' proprietary software.

FIG. 6 shows typical X-ray powder diffraction patterns for Form I (plot(a)) and Form II (plot(b)) of compound 41. Table 1 shows a summarycomparison of prominent X-ray powder diffraction peaks for Form I andForm II.

TABLE 1 Form I Relative Form II 2-Theta Peak 2-Theta Relative Peak ValueIntensity (%) Value Intensity (%) 7.203 15.0665 9.1962 18.6166 8.4529.0688 12.277 29.2318 9.726 37.1457 12.584 8.39048 11.205 49.020712.833 7.67902 11.786 10.8439 13.872 100 12.51 15.9267 14.286 77.568213.342 11.0306 15.168 7.54978 14.25 16.3005 15.641 16.0194 14.85916.1351 15.935 11.4935 15.526 43.0987 16.138 16.6656 15.874 25.42416.399 36.1255 16.309 14.278 16.544 77.6935 17.121 14.1898 17.09413.1102 17.498 13.173 17.645 38.4531 18.542 99.3626 18.511 33.022619.354 85.1982 18.826 91.0787 19.789 16.7251 19.128 25.2644 20.3439.3083 19.327 18.8639 20.891 27.5965 19.906 38.7122 21.297 16.226620.085 12.7865 22.022 26.6845 20.23 10.2004 23.304 42.0171 21.00 8.5843325.125 17.2159 21.48 47.6981 25.734 18.2944 21.729 33.6048 27.50325.8376 22.089 12.1403 32.056 12.7407 22.4 10.0712 35.188 22.4211 22.74813.3041 40.166 16.7913 22.959 14.5971 23.22 13.498 23.472 17.8224 23.96516.9247 24.553 16.8594 25.038 9.6835 25.299 13.0904 25.626 13.950325.767 14.9202 25.887 11.2996 26.343 18.1531 26.873 9.87736 27.94115.1787 28.228 15.4437 28.815 11.2996 29.475 13.7532 34.758 21.77340.176 21.0731

EXAMPLE 113 Fourier Transform Infrared Spectra

The Fourier transform infrared (FTIR) spectra for Form I and Form II ofcompound 41 are obtained using a Bio-Rad FTS-45 Fourier-transforminfrared spectrometer equipped with a micro-ATR (attenuated totalreflectance) beam condensing accessory (IBM Corporation) mounted in thesample compartment of the instrument. The sample compartment and opticalbench of the spectrometer is under a nitrogen purge. The software usedfor operating the instrument and collecting the spectrum is Bio-Rad'sWindows 98-based Win-IR software. The spectra are obtained using an8-wavenumber resolution and 16 scans.

A small amount of sample is placed onto one side of a 5×10×1 mm KRS5 (atype of infrared transmitting material commonly used in the IR world)ATR crystal, and lightly tamped with a stainless steel micro spatula inorder to ensure good contact of the sample with the face of the crystal.The crystal is mounted into the ATR beam-condensing accessory, and thesample compartment allowed to purge for a few minutes to remove watervapor and carbon dioxide (their presence reduces the quality of thespectrum). This can be monitored on the screen of the operating console,and when down to an acceptable level, the 16 scans are collected toproduce an interferogram. Prior to analyzing the sample, a clean KRS5crystal is mounted in the ATR accessory and a background interferogramcollected. The purge time and number of scans for collecting thebackground should be the same as will be used for analyzing the sample.

The Fourier-transform of the resulting interferogram is automaticallydone and the spectrum appears on the screen. The resulting spectrum isthen smoothed and baseline corrected, if necessary, then ATR correctedto obtain a spectrum that is comparable to an absorption or transmissionspectrum.

FIG. 7 shows typical FTIR spectra for Form I (plot (a)) and Form II(plot (b)) of compound 41. Table 2 shows a summary comparison ofprominent FTIR peaks for Form I and Form II.

TABLE 2 Form I Peaks Form II Peaks (cm⁻¹) (cm⁻¹) 3163 3250 2870 28851596 1600 1300 1288 1239 1225 1182 1172 1055 1050  986  990  855  858 825  837  627  620

EXAMPLE 114 Solid-state Carbon-13 NMR Analysis

Solid-state NMR. Cross-polarization magic-angle spinning (CPMAS) ¹³C NMRspectra were collected on a Monsanto-built spectrometer operating at aproton resonance frequency of 127.0 MHz. Samples were spun at the magicangle with respect to the magnetic field in a double-bearing rotorsystem at a rate of 3 kHz. CPMAS ¹³C NMR spectra were obtained at 31.9MHz following 2-ms matched, 50-kHz ¹H-¹³C cross-polarization contacts.High-power proton dipolar decoupling (H₁(H)=65-75 kHz) was used duringdata acquisition. Residual spinning sidebands were suppressed using theTotal Suppression of Sidebands (TOSS) method. In each experiment,approximately 219 mg of Form I and approximately 142 mg Form II areused.

FIG. 8 shows typical solid-state ¹³C nuclear magnetic resonance (NMR)spectra for Form I (plot (a)) and Form II (plot (b)) of compound 41.Table 3 shows a summary comparison of prominent solid-state ¹³C NMRpeaks for Form I and Form II.

TABLE 3 Form I (ppm) Form II (ppm) 158.55 157.971 151.712 142.325145.986 137.172 140.852 134.043 136.628 127.232 133.489 125.390 128.151118.212 120.052 113.057 115.266 106.615 113.241 76.795 109.928 68.51276.795 57.100 68.860 47.712 54.523 43.661 46.239 37.951 43.847 21.94240.901 14.763 24.519 13.281 14.395 3.351

EXAMPLE 115 Water Uptake Experiments

Water sorption experiments are performed on a Dynamic Vapor Sorption(DVS) apparatus (DVS-1000 manufactured by Surface Measurements Systems,Inc.). Experiments are performed at 25° C. by initially drying thematerial of interest (about 10 mg sample) from 30% relative humidity(RH) (ambient room condition) to about 9% RH in a stepwise fashion (10%RH step) by purging with dry nitrogen until no further weight change wasobserved. The samples are then exposed to a stepwise (10% RH steps)increase in RH from about 0 to about 90% RH. Each successive step isinitiated when the change in weight over time at the relative humiditywas less than 0.0003% ((dm/dt)/m₀×100, where m is mass in mg, m₀ isinitial mass, and t is time in minutes). The sample is then takenthrough the reverse of the stepwise % RH increase. The data arecollected on a computer and analyzed using SMS' proprietary MS-Excelmacro interface software. FIG. 10 shows typical water sorption isothermresults for Form I (plot (a)) and Form II (plot (b)) of compound 41.Table 4 shows a summary comparison of water sorption and desorptionisotherms for Form I and Form II at 25° C.

TABLE 4 Sorption % Desorptoin % % RH at 25° C. Weight Change WeightChange Form I 0.45 0.057 0.057 9.2 0.9575 0.997 20.05 2.016 2.1025 29.753.4105 3.599 39.4 4.282 4.743 49.55 4.928 5.321 59.4 5.356 5.726 69.055.706 6.054 78.8 6.109 6.357 88.5 6.734 6.734 Form II 1.3 −0.02695−0.02695 9.35 0.04715 0.04235 20.25 0.10585 0.09715 29.75 0.137550.14435 39.55 0.1809 0.1866 49.7 0.2386 0.2636 59.5 0.304 0.331 69.10.3945 0.3983 78.65 0.4695 0.4849 88.5 0.6446 0.6446

The examples herein can be performed by substituting the generically orspecifically described reactants and/or operating conditions of thisinvention for those used in the preceding examples.

The invention being thus described, it is apparent that the same can bevaried in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the present invention, and allsuch modifications and equivalents as would be obvious to one skilled inthe art are intended to be included within the scope of the followingclaims.

What is claimed is:
 1. A crystalline form of a tetrahydrobenzothiepinecompound having the structure of Formula 71

or an enantiomer thereof wherein the crystalline form has a meltingpoint or a decomposition point of about 278° C. to about 285° C.
 2. Thecrystalline form of claim 1 wherein the tetrahydrobenzothiepine compoundhas an absolute configuration predominantly of (4R,5R).
 3. Thecrystalline form of claim 1 having a melting point or a decompositionpoint of about 280° C. to about 283° C.
 4. The crystalline form of claim3 having a melting point or a decomposition point of about 282° C. 5.The crystalline form of claim 1 having an X-ray powder diffractionpattern with peaks at about 9.2 degrees 2 theta, about 12.3 degrees 2theta, and about 13.9 degrees 2 theta.
 6. The crystalline form of claim5 wherein the X-ray powder diffraction pattern substantially lacks peaksat about 7.2 degrees 2 theta and at about 11.2 degrees 2 theta.
 7. Thecrystalline form of claim 1 having an X-ray powder diffraction patternsubstantially as shown in plot (b) of FIG.
 6. 8. The crystalline form ofclaim 1 having an IR spectrum with a peak at about 3245 cm⁻¹ to about3255 cm⁻¹.
 9. The crystalline form of claim 8 having an IR spectrum witha peak at about 1600 cm⁻¹.
 10. The crystalline form of claim 8 having anIR spectrum with a peak at about 1288 cm⁻¹.
 11. The crystalline form ofclaim 8 having an IR spectrum substantially as shown in plot (b) of FIG.7.
 12. The crystalline form of claim 1 having a solid state carbon-13NMR spectrum with peaks at about 142.3 ppm, about 137.2 ppm, and about125.4 ppm.
 13. The crystalline form of claim 1 having a solid statecarbon-13 NMR spectrum substantially as shown in plot (b) of FIG.
 8. 14.The crystalline form of claim 1 that after an essentially dry sample ofthe crystalline form is equilibrated under about 80% relative humidityair at 25° C. gains less than 1% of its own weight.
 15. The crystallineform of claim 1 that is essentially nonhygroscopic.
 16. A crystallineform of a tetrahydrobenzothiepine compound wherein thetetrahydrobenzothiepine compound has the structure of Formula 71

and that after a sample of the crystalline form is dried at essentially0% relative humidity at about 25° C. under a purge of essentially drynitrogen until the sample exhibits essentially no weight change as afunction of time, the sample gains less than 1% of its own weight whenequilibrated under about 80% relative humidity air at about 25° C.
 17. Acrystalline form of a tetrahydrobenzothiepine compound wherein thetetrahydrobenzothiepine compound has the structure of Formula 71

and wherein the crystalline form is produced by crystallizing thetetrahydrobenzothiepine compound from a solvent comprising methyl ethylketone.
 18. A method for the preparation of a crystalline form of atetrahydrobenzothiepine compound having the structure of Formula 63

wherein the method comprises crystallizing the tetrahydrobenzothiepinecompound from a solvent comprising methyl ethyl ketone, and wherein: R¹and R² independently are C₁ to about C₂₀ hydrocarbyl; R³, R⁴, and R⁵independently are selected from the group consisting of H and C₁ toabout C₂₀ hydrocarbyl, wherein optionally one or more carbon atom of thehydrocarbyl is replaced by O, N, or S, and wherein optionally two ormore of R³, R⁴, and R⁵ taken together with the atom to which they areattached form a cyclic structure; R⁹ is selected from the groupconsisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl,heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR³, NR³R⁴,N⁺R³R⁴R⁵A⁻, SR³, S(O)R³, SO₂R³, SO₃R³, oxo, CO₂R³, CN, halogen, NCO,CONR³R⁴, SO₂OM, SO₂NR³R⁴, PO(OR²³)OR²⁴, P⁺R³R⁴R⁵A⁻, S⁺R³R⁴A⁻, andC(O)OM; R²³ and R²⁴ are independently selected from the substituentsconstituting R³ and M; n is a number from 0 to 4; A⁻ and Z⁻independently are pharmaceutically acceptable anions; and M is apharmaceutically acceptable cation.
 19. The method of claim 18 whereinthe tetrahydrobenzothiepine compound has the structure of Formula 64


20. The method of claim 19 wherein the tetrahydrobenzothiepine compoundhas the structure of Formula 41


21. A method for the preparation of a product crystal form of atetrahydrobenzothiepine compound having the compound structure ofFormula 41

wherein the product crystal form has a melting point or a decompositionpoint of about 278° C. to about 285° C., wherein the method comprisesapplying heat to an initial crystal form of the tetrahydrobenzothiepinecompound wherein the initial crystal form has a melting point or adecomposition point of about 220° C. to about 235° C., thereby formingthe product crystal form.
 22. The method of claim 21 wherein the initialcrystal form is heated to a temperature from about 20° C. to about 150°C.
 23. The method of claim 22 wherein the initial crystal form is heatedto a temperature from about 50° C. to about 125° C.
 24. The method ofclaim 23 wherein the initial crystal form is heated to a temperaturefrom about 60° C. to about 100° C.
 25. The method of claim 21 whereinthe method further comprises a cooling step after the step in which theinitial crystal form is heated.
 26. The method of claim 21 furthercomprising mixing the initial crystal form with a solvent.
 27. Themethod of claim 26 wherein the solvent comprises a ketone.
 28. Themethod of claim 27 wherein the ketone is selected from the groupconsisting of methyl ethyl ketone, acetone, and methyl isobutyl ketone.29. The method of claim 28 wherein the ketone is methyl ethyl ketone.30. The method of claim 28 wherein the ketone is acetone.
 31. The methodof claim 28 wherein the ketone is methyl isobutyl ketone.
 32. The methodof claim 26 wherein the method further comprises a cooling step afterthe step in which the initial crystal form is heated.